Synthesis of polycyclic-carbamoylpyridone compounds

ABSTRACT

Methods of making compounds of Formula I are disclosed:

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of application Ser. No. 15/639,833,filed Jun. 30, 2017, which is a Continuation of application Ser. No.14/740,954, filed Jun. 16, 2015. Application Ser. No. 14/740,954 claimsthe benefit of U.S. Provisional Application No. 62/015,081, filed Jun.20, 2014. The entire contents of these applications are incorporatedherein by reference in their entirety.

BACKGROUND Field

Novel methods of synthesis of polycyclic carbamoylpyridone compounds aredisclosed. Intermediates in the synthetic pathway of polycycliccarbamoylpyridone compound are also disclosed.

Description of the Related Art

Human immunodeficiency virus infection and related diseases are a majorpublic health problem worldwide. Human immunodeficiency virus type 1(HIV-1) encodes three enzymes which are required for viral replication:reverse transcriptase, protease, and integrase. Although drugs targetingreverse transcriptase and protease are in wide use and have showneffectiveness, particularly when employed in combination, toxicity anddevelopment of resistant strains have limited their usefulness (Palella,et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001)410:995-1001). Accordingly, there is a need for new agents that inhibitthe replication of HIV and that minimize PXR activation whenco-administered with other drugs.

Certain polycyclic carbamoylpyridone compounds have been found to haveantiviral activity, as disclosed in PCT/US2013/076367. Accordingly,there is a need for synthetic routes for such compounds.

SUMMARY

The present invention is directed to a novel synthetic process forpreparing the polycyclic carbamoylpyridone compounds of Formula I usingthe synthetic steps described herein. The present invention is alsodirected to particular individual steps of this process and particularindividual intermediates used in this process. One embodiment of thepresent invention provides a process to prepare a Compound of Formula I:

A further embodiment provides a process to prepare a Compound of FormulaI

according to the following General Scheme I:

wherein the process comprises the following steps:

-   -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid and N-1, or salts or        co-crystals thereof, in the presence of a base to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I;

wherein

-   -   Hal is halogen, which may be the same or different,    -   n is 1, 2, or 3,    -   L is —C(R^(c))₂—, —C(R^(c))₂C(R^(c))₂—,        —C(R^(c))₂C(R^(c))₂C(R^(c))₂—, or        —C(R^(c))₂C(R^(c))₂C(R^(c))₂C(R^(c))₂—,    -   each R^(c) is, independently, hydrogen, halo, hydroxyl or        C₁-C₄alkyl,    -   each R^(a), R¹, and R² is, independently, (C₁-C₄)alkyl,        (C₂-C₁₀)aryl, or (C₂-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, each R^(b) is independently (C₁-C₄)alkyl.

In some embodiments, each R^(a), R¹, and R² is, independently,(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl.

Another embodiment provides a process to prepare a compound of Formula I

according to the following General Scheme II:

wherein the process comprises the following steps:

-   -   reacting A-1 with H-1 in the presence of a catalyst, a base, and        an acylating reagent to yield B-1;    -   reacting B-1 with J-1 in the presence of an acid to yield C-1;    -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid and N-1, in the presence of        a base to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I;

wherein

-   -   Hal is halogen,    -   n is 1, 2, or 3,    -   L is —C(R^(c))₂—, —C(R^(c))₂C(R^(c))₂—,        —C(R^(c))₂C(R^(c))₂C(R^(c))₂—, or        —C(R^(c))₂C(R^(c))₂C(R^(c))₂C(R^(c))₂—,    -   each R^(c) is, independently, hydrogen, halo, hydroxyl or        C₁-C₄alkyl,    -   each R^(a), R^(b), R¹, and R² is, independently(C₁-C₄)alkyl,        (C₂-C₁₀)aryl, or (C₂-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, Hal is halogen, which may be the same or different.

In some embodiments, each R^(a), R^(b), R¹, and R² is, independently,(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, J-1 is in the form of a salt or a co-crystal.

In some embodiments, N-1 is in the form of a salt or a co-crystal.

Another embodiment provides a process to prepare a Compound of Formula I

according to the following General Scheme III:

wherein the process comprises the following steps:

-   -   reacting B-1 with Q-1 to yield BB-1 reacting BB-1 with J-1 to        yield C-1;    -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid and N-1, or salts or        co-crystals thereof, in the presence of a base to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I;        wherein    -   Hal is halogen,    -   n is 1, 2, or 3,    -   L is —C(R^(c))₂—, —C(R^(c))₂C(R^(c))₂—,        —C(R^(c))₂C(R^(c))₂C(R^(c))₂—, or        —C(R^(c))₂C(R^(c))₂C(R^(c))₂C(R^(c))₂—,    -   each R^(c) is, independently, hydrogen, halo, hydroxyl or        C₁-C₄alkyl,    -   each R^(a), R^(b), R^(d), R¹, and R² is, independently,        (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or (C₂-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, Hal is halogen, which may be the same or different.

In some embodiments, each R^(a), R^(b), R^(d), R¹, and R² is,independently, (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, J-1 is in the form of a salt or a co-crystal.

Another embodiment provides a process to prepare a Compound of Formula I

according to the following General Scheme IV:

wherein the process comprises the following steps:

-   -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with M-1 to yield EE-1;    -   reacting EE-1 with K-1 to yield F-1;    -   reacting F-1 with at least one acid and N-1, in the presence of        a base to yield G-1;    -   reacting G-1 under conditions suitable yield a compound of        Formula I;        wherein    -   Hal is halogen,    -   n is 1, 2, or 3,    -   L is —C(R^(c))₂—, —C(R^(c))₂C(R^(c))₂—,        —C(R^(c))₂C(R^(c))₂C(R^(c))₂—, or        —C(R^(c))₂C(R^(c))₂C(R^(c))₂C(R^(c))₂—,    -   each R^(a) is, independently, hydrogen, halo, hydroxyl or        C₁-C₄alkyl,    -   each R^(a), R^(b), R¹, and R² is, independently, (C₁-C₄)alkyl,        (C₂-C₁₀)aryl, or (C₂-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, Hal is halogen, which may be the same or different.

In some embodiments, each R^(a), R^(b), R¹, and R² is, independently,(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, N-1 is in the form of a salt or a co-crystal.

Another embodiment provides a process to prepare a compound of FormulaII:

according to the following General Scheme V:

wherein the process comprises the following steps:

-   -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with a base to yield a compound of Formula II,        wherein    -   Hal is halogen,    -   n is 1, 2, or 3,    -   each Ru, R^(b), R¹, and R² is, independently, (C₁-C₄)alkyl,        (C₂-C₁₀)aryl, or (C₂-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, Hal is halogen, which may be the same or different.

In some embodiments, each R^(a), R^(b), R¹, and R² is, independently,(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₄)alkyl.

Another embodiment provides a process to prepare a Compound of FormulaI:

according to the following General Scheme VI

wherein the process comprises the following steps:

-   -   reacting B-1.J-1 under conditions suitable to yield C-1;    -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid to yield FF-1;    -   reacting FF-1 with N-1, or salts or co-crystals thereof, in the        presence of an additive to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I;        wherein    -   Hal is halogen, which may be the same or different,    -   n is 1, 2, or 3,    -   L is —C(R^(c))₂—, —C(R^(c))₂C(R^(c))₂—,        —C(R^(c))₂C(R^(c))₂C(R^(c))₂—, or        —C(R^(c))₂C(R^(c))₂C(R^(c))₂C(R^(c))₂—,    -   each R^(c) is, independently, hydrogen, halo, hydroxyl or        C₁-C₄alkyl,    -   each R^(b) is, independently C₁-C₄alkyl,    -   each R^(a), R¹, and R² is, independently, (C₁-C₄)alkyl,        (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl.

Other embodiments and features will be set forth in the detaileddescription of the embodiments that follows, and in part will beapparent from the description, or may be learned by practice, of theclaimed invention. The foregoing summary has been made with theunderstanding that it is to be considered as a brief and generalsynopsis of some of the embodiments disclosed herein, is provided solelyfor the benefit and convenience of the reader, and is not intended tolimit in any manner the scope, or range of equivalents, to which theappended claims are lawfully entitled.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. The description below of severalembodiments is made with the understanding that the present disclosureis to be considered as an exemplification of the claimed subject matter,and is not intended to limit the appended claims to the specificembodiments illustrated. The headings used throughout this disclosureare provided for convenience only and are not to be construed to limitthe claims in any way. Embodiments illustrated under any heading may becombined with embodiments illustrated under any other heading.

Definitions

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

A prefix such as “C_(u-v)” or (C_(u)-C_(v)) indicates that the followinggroup has from u to v carbon atoms. For example, “(C₁-C₆)alkyl”indicates that the alkyl group has from 1 to 6 carbon atoms and(C₆-C₁₀)aryl(C₁-C₆)alkyl indicates that the aryl portion of the grouphas from 6 to 10 carbon atoms and the alkyl portion of the group hasfrom one to six carbon atoms.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“BzOH” refers to benzoic acid or

“Alkyl” refers to a straight or branched saturated hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms (C₁-C₁₂ alkyl), or one to eight carbon atoms(C₁-C₈ alkyl), or one to six carbon atoms (C₁-C₆ alkyl), or one to 4carbon atoms (C₁-C₄ alkyl) and which is attached to the rest of themolecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl,pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl,hexynyl, and the like. Unless stated otherwise specifically in thespecification, an alkyl group may be optionally substituted.

In some embodiments, “Alkyl” refers to a straight or branched saturatedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, having from one to twelve carbon atoms (C₁-C₁₂ alkyl), or one toeight carbon atoms (C₁-C₈ alkyl), or one to six carbon atoms (C₁-C₆alkyl), or one to 4 carbon atoms (C₁-C₄ alkyl) and which is attached tothe rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted.

“Alkenyl” refers to any group derived from a straight or branchedhydrocarbon with at least one carbon-carbon double bond. Alkenyl groupsinclude, but are not limited to, ethenyl (vinyl), propenyl (allyl),1-butenyl, 1,3-butadienyl, and the like. Unless otherwise specified, analkenyl group has from 2 to about 10 carbon atoms, for example from 2 to10 carbon atoms, for example from 2 to 6 carbon atoms, for example from2 to 4 carbon atoms.

“Alkynyl” refers to any group derived from a straight or branchedhydrocarbon with at least one carbon-carbon triple bond and includesthose groups having one triple bond and one double bond. Examples ofalkynyl groups include, but are not limited to, ethynyl (—C≡CH),propargyl (—CH₂C≡CH), (E)-pent-3-en-1-ynyl, and the like. Unlessotherwise specified, an alkynyl group has from 2 to about 10 carbonatoms, for example from 2 to 10 carbon atoms, for example from 2 to 6carbon atoms, for example from 2 to 4 carbon atoms.

“Alkoxy” refers to a radical of the formula —OR^(A) where R^(A) is analkyl radical as defined above containing one to twelve carbon atoms, orone to eight carbon atoms, or one to six carbon atoms, or one to fourcarbon atoms. Unless stated otherwise specifically in the specification,an alkoxy group may be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR^(A) or —NR^(A)R^(A)where each R_(A) is, independently, an alkyl radical as defined abovecontaining one to twelve carbon atoms, or one to eight carbon atoms, orone to six carbon atoms, or one to four carbon atoms. Unless statedotherwise specifically in the specification, an alkylamino group may beoptionally substituted.

“Thioalkyl” refers to a radical of the formula —SR^(A) where R^(A) is analkyl radical as defined above containing one to twelve carbon atoms, orone to eight carbon atoms, or one to six carbon atoms, or one to fourcarbon atoms. Unless stated otherwise specifically in the specification,a thioalkyl group may be optionally substituted.

“Aryl” refers to a monocyclic hydrocarbon ring system radical comprisinghydrogen and 6 to 18 carbon atoms, or 6 to 10 carbon atoms or 6 to 8carbon atoms. Aryl radicals include, but are not limited to, arylradicals derived from benzene. Unless stated otherwise specifically inthe specification, the term “aryl” or the prefix “ar-” (such as in“aralkyl”) is meant to include aryl radicals that are optionallysubstituted.

“Arylalkyl” (also “aralkyl”) refers to a radical of the formula—R^(B)—R^(C) where R^(B) is an alkyl group as defined above and R_(C) isone or more aryl radicals as defined above, for example, benzyl.Arylalkyl groups include, but are not limited to, those groups derivedfrom benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl,2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronapthyl, and thelike. An arylalkyl group comprises from 6 to about 30 carbon atoms, forexample the alkyl group can comprise from 1 to about 10 carbon atoms andthe aryl group can comprise from 5 to about 20 carbon atoms. Unlessstated otherwise specifically in the specification, an aralkyl group maybe optionally substituted.

In some embodiments, “Arylalkyl” (also “aralkyl”) refers to a radical ofthe formula —R^(B)-R^(C) where R^(B) is an alkyl group as defined aboveand R^(C) is one or more aryl radicals as defined above, for example,benzyl. Arylalkyl groups include, but are not limited to, those groupsderived from benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl,2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronapthyl, and thelike. An arylalkyl group comprises from 6 to about 30 carbon atoms, forexample the alkyl group can comprise from 1 to about 10 carbon atoms andthe aryl group can comprise from 6 to about 20 carbon atoms. Unlessstated otherwise specifically in the specification, an aralkyl group maybe optionally substituted.

“Cycloalkyl” refers to a cyclic alkyl group. A cycloalkyl group can haveone or more cyclic rings and includes fused and bridged groups. Examplesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, adamantyl, and the like. Unless otherwise statedspecifically in the specification, a carbocyclic group may be optionallysubstituted.

“Carbocyclic ring” or “carbocycle” refers to a stable non-aromaticmonocyclic hydrocarbon radical consisting solely of carbon and hydrogenatoms, having from three to fifteen carbon atoms, preferably having fromthree to ten carbon atoms, and which is saturated or unsaturated andattached to the rest of the molecule by a single bond. Monocyclicradicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise statedspecifically in the specification, a carbocyclic group may be optionallysubstituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(B)R_(D) whereR_(B) is an alkyl group as defined above and R^(D) is a carbocyclicradical as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group may be optionally substituted.

In some embodiments, “Cycloalkylalkyl” refers to a radical of theformula —R_(B)R_(D) where R_(B) is an alkyl group as defined above andR_(D) is a carbocyclic radical as defined above. Unless stated otherwisespecifically in the specification, a cycloalkylalkyl group may beoptionally substituted.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group may be optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring radical which consists of two to twelvecarbon atoms and from one to six heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. In some embodiments, theheterocyclyl radical is a 3 to 12 membered non-aromatic ring, or a 3 to8 membered non-aromatic ring, or a 3 to 6 membered non-aromatic ring. Insome embodiments, the heterocyclyl radical contains one to fourheteroatoms, or one to three heteroatoms, or one to two heteroatoms, orone heteroatom. In the embodiments disclosed herein, the heterocyclylradical is a monocyclic ring system; and the heterocyclyl radical may bepartially or fully saturated. Examples of such heterocyclyl radicalsinclude, but are not limited to, dioxolanyl, thienyl, [1,3]dithianyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl,pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification, a heterocyclyl group may beoptionally substituted.

In some embodiments, “Heterocyclyl” or “heterocyclic ring” refers to astable 4- to 18-membered non-aromatic ring radical which consists of 3to 17 carbon atoms and from one to six heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur. In some embodiments,the heterocyclyl radical is a 4 to 12 membered non-aromatic ring, or a 4to 8 membered non-aromatic ring, or a 4 to 6 membered non-aromatic ring.In some embodiments, the heterocyclyl radical contains one to fourheteroatoms, or one to three heteroatoms, or one to two heteroatoms, orone heteroatom. Unless stated otherwise specifically in thespecification, a heterocyclyl group may be optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, an N-heterocyclyl group may beoptionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(B)R_(E) whereR_(B) is an alkylgroup as defined above and R_(E) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. Unless stated otherwisespecifically in the specification, a heterocyclylalkyl group may beoptionally substituted.

“Heteroaryl” refers to an aryl group in which one or more of the carbonatoms (and any associated hydrogen atoms) are each independentlyreplaced with the the same or different heteroatom selected from thegroup consisting of nitrogen, oxygen and sulfur. Unless otherwisespecified, an heteroaryl group has from 5 to about 20 carbon atoms, forexample from 5 to 18 carbon atoms, for example from 5 to 14 carbonatoms, for example from 5 to 10 carbon atoms. Heteroaryl groups havefrom one to six heteroatoms, from one to four heteroatoms, from one tothree heteroatoms, from one to two heteroatoms or one heteroatom. Unlessstated otherwise specifically in the specification, a heteroaryl groupmay be optionally substituted.

In some, embodiments, “Heteroaryl” refers to an aryl group in which oneor more of the carbon atoms (and any associated hydrogen atoms) are eachindependently replaced with the the same or different heteroatomselected from the group consisting of nitrogen, oxygen and sulfur.Heteroaryl groups include, but are not limited to, groups derived fromfuran, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, tetrazole,thiadiazole, thiazole, thiophene, triazole, and the like. Unlessotherwise specified, an heteroaryl group has from 5 to about 20 carbonatoms, for example from 5 to 18 carbon atoms, for example from 5 to 14carbon atoms, for example from 5 to 10 carbon atoms. Heteroaryl groupshave from one to six heteroatoms, from one to four heteroatoms, from oneto three heteroatoms, from one to two heteroatoms or one heteroatom.Unless stated otherwise specifically in the specification, a heteroarylgroup may be optionally substituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group may be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(B)R_(F) whereR_(B) is an alkyl group as defined above and R_(F) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group may be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,carbocycle, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl)wherein at least one hydrogen atom is replaced by a bond to anon-hydrogen atoms such as, but not limited to: a halogen atom such asF, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups,alkoxy groups, and ester groups; a sulfur atom in groups such as thiolgroups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxidegroups; a nitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. For example, “substituted” includes any of theabove groups in which one or more hydrogen atoms are replaced with—NR_(G)R_(H), —NR_(G)C(═O)R_(H), —NR_(G)C(═O)NR_(G)R_(H),—NR_(G)C(═O)OR_(H), —NR_(G)C(═NR_(g))NR_(G)R_(H), —NR_(G)SO₂R_(H),—OC(═O)NR_(G)R_(H), —OR_(G), —SR_(G), —SOR_(G), —SO₂R_(G), —OSO₂R_(G),—SO₂OR_(G), ═NSO₂R_(G), and —SO₂NR_(G)R_(H). “Substituted also means anyof the above groups in which one or more hydrogen atoms are replacedwith —C(═O)R_(G), —C(═O)OR_(G), —C(═O)NR_(G)R_(H), —CH₂SO₂R_(G),—CH₂SO₂NR_(G)R_(H). In the foregoing, R_(G) and R_(H) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, carbocycle, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any ofthe above groups in which one or more hydrogen atoms are replaced by abond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocycle,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. In addition, each of the foregoing substituents may also beoptionally substituted with one or more of the above substituents.

The term “alkylated formamide acetal” as used herein, refers to acompound of Formula:

wherein each R^(b) is independently (C₁-C₄)alkyl, R^(v1) and R^(v2) areindependently (C₁-C₆)alkyl or R^(v1) and R^(v2) together with the atomsto which they are attached form a 5 to 10 membered heterocyclyl.

“Alkylated formamide acetal” includes, but is not limited toN,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethylacetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamidedimethyl acetal, and N,N-diisopropylformamide dimethyl acetal.

The term “acyl donor” as used herein, refers to a reactive compoundwhich transfers a group —CO—R^(x) onto another molecule, wherein R^(x)is (C₁-C₆)alkyl-R^(y) and R^(y) is selected from the group consisting ofH, CN, —NR^(z1)R^(z2), C(O)R^(z1), —C(O)OR^(z1), —C(O)NR^(z1)R^(z2),—OC(O)NR^(z1)R^(z2), —NR^(z1)C(O)R^(z2), —NR^(z1), C(O)NR^(z2),—NR^(z1)C(O)OR^(z2), —S(O)₁₋₂R^(z1), —S(O)₂NR^(z1)R^(z2), S(O)₂R^(z2),NR^(z1)S(O)₂R^(z2), and OR^(z1) and R^(z2) are independently selectedfrom the group consisting of H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, 3 to 12 membered heterocyclyl,C₆₋₁₀aryl and 5 to 10 membered heteroaryl. In certain embodiments, R^(y)is H. In certain embodiments, R^(z1) and R^(z2) are independentlyselected from the group consisting of H and C₁₋₆alkyl. Acyl donorsinclude but are not limited to anhydrides, esters and acid chloridessuch as succinic anhydride, glutaric anhydride, acetic anhydride, vinylacetate, isopropenyl acetate, 4-chlorophenyl acetate, ethyl methoxyacetate, acetyl chloride and benzoyl chloride.

A person skilled in the art will understand that throughout thisapplication, and more specifically in Schemes I, II, III, V and VI,compound E-1 may exist in an E or in a Z configuration or as a mixtureof an E and Z configuration. Accordingly, in certain embodiments,compound E-1 is in an E or a Z configuration, or a mixture thereof. Incertain embodiments, compound E-1 is in an E configuration. In certainembodiments, compound E-1 is in an Z configuration. In certainembodiments, compound E-1 is in a mixture of Z and E configurations.

A person skilled in the art will understand that throughout thisapplication, compound B-1.J-1 is a salt:

The term “protecting group,” as used herein, refers to a labile chemicalmoiety which is known in the art to protect reactive groups includingwithout limitation, hydroxyl and amino groups, against undesiredreactions during synthetic procedures. Hydroxyl and amino groupsprotected with a protecting group are referred to herein as “protectedhydroxyl groups” and “protected amino groups”, respectively. Protectinggroups are typically used selectively and/or orthogonally to protectsites during reactions at other reactive sites and can then be removedto leave the unprotected group as is or available for further reactions.Protecting groups as known in the art are described generally in Greeneand Wuts, Protective Groups in Organic Synthesis, 3rd edition, JohnWiley & Sons, New York (1999). Generally, groups are protected orpresent as a precursor that will be inert to reactions that modify otherareas of the parent molecule for conversion into their final groups atan appropriate time. Further representative protecting or precursorgroups are discussed in Agrawal, et al., Protocols for OligonucleotideConjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72.Examples of “hydroxyl protecting groups” include, but are not limitedto, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethy lsilylethyl,p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl,diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS),triphenylsilyl, benzoylformate, acetate, chloroacetate,trichloroacetate, trifluoroacetate, pivaloate, benzoate,p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate.Examples of “amino protecting groups” include, but are not limited to,carbamate-protecting groups, such as 2-trimethylsilylethoxycarbonyl(Teoc), 1-methyl-1-(4-biphenylyl)ethoxy-carbonyl (Bpoc),t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluoreny lmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protectinggroups, such as formyl, acetyl, trihaloacetyl, benzoyl, andnitrophenylacetyl; sulfonamide-protecting groups, such as2-nitrobenzenesulfonyl; and imine and cyclic imide protecting groups,such as phthalimido and dithiasuccinoyl.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of Formula I and compounds ofFormula II being isotopically-labeled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabeled compounds could be useful to helpdetermine or measure the effectiveness of the compounds, bycharacterizing, for example, the site or mode of action, or bindingaffinity to pharmacologically important site of action. Certainisotopically-labeled compounds of Formula I and compounds of Formula II,for example, those incorporating a radioactive isotope, are useful indrug and/or substrate tissue distribution studies. The radioactiveisotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability. For example, in vivo half-life may increase or dosagerequirements may be reduced. Thus, heavier isotopes may be preferred insome circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof Formula I and compounds of Formula II can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the Examples as set out belowusing an appropriate isotopically-labeled reagent in place of thenon-labeled reagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabeled compound described in the embodimentsherein in a detectable dose to an animal, such as rat, mouse, guineapig, monkey, or to human, allowing sufficient time for metabolism tooccur, and isolating its conversion products from the urine, blood orother biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Lewis acid” refers to a group that can accept a nonbonding pair ofelectrons, i.e., an electron-pair acceptor. Lewis acids are able toreact with a Lewis base to form a Lewis adduct, by sharing the electronpair supplied by the Lewis base.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses (or can be convertedto a form that possesses) the desired pharmacological activity of theparent compound. Examples of “pharmaceutically acceptable salts” of thecompounds disclosed herein include salts derived from an appropriatebase, such as an alkali metal (for example, sodium), an alkaline earthmetal (for example, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an aminogroup include for example salts of organic carboxylic acids such asacetic, benzoic, camphorsulfonic, citric, glucoheptonic, gluconic,lactic, fumaric, tartaric, maleic, malonic, malic, mandelic, isethionic,lactobionic, succinic, 2-napththalenesulfonic, oleic, palmitic,propionic, stearic, and trimethylacetic acids; organic sulfonic acids,such as methanesulfonic, ethanesulfonic, benzenesulfonic andp-toluenesulfonic acids; and inorganic acids, such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and sulfamic acids.Pharmaceutically acceptable salts of a compound of a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group). Pharmaceutically acceptable salts also include saltsformed when an acidic proton present in the parent compound is replacedby either a metal ion, e.g., an alkali metal ion, an alkaline earth ion,or an aluminum ion; or coordinates with an organic base such asdiethanolamine, triethanolamine, N-methylglucamine and the like. Alsoincluded in this definition are ammonium and substituted or quaternizedammonium salts. Representative non-limiting lists of pharmaceuticallyacceptable salts can be found in S. M. Berge et al., J. Pharma Sci.,66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy,R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins,Philadelphia, Pa., (2005), at p. 732, Table 38-5, both of which arehereby incorporated by reference herein.

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of Formula I, a compound of Formula II oranother compound described herein. All salts, whether or not derivedfrom a physiologically acceptable acid or base, are within the scope ofthe present invention.

Metal salts refer to salts wherein the cation is a metal, such as thoseformed when an acidic proton present in a compound is replaced by eithera metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminium ion; or a metal ion coordinates with an organic base such asdiethanolamine, triethanolamine, N-methylglucamine and the like.

The metal can be an alkali metal, alkaline earth metal, transitionmetal, or main group metal. Non-limiting examples of suitable metalsinclude lithium, sodium, potassium, cesium, cerium, magnesium,manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper,cadmium, and zinc.

Non-limiting examples of suitable metal salts include a lithium salt, asodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesiumsalt, a manganese salt, an iron salt, a calcium salt, a strontium salt,a cobalt salt, a titanium salt, a aluminum salt, a copper salt, acadmium salt, and a zinc salt.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines.

Finally, it is to be understood that the compositions herein comprisecompounds disclosed herein in their un-ionized, as well as zwitterionicform, and combinations with stoichiometric amounts of water as inhydrates.

Often crystallizations produce a solvate of the compound described inthe embodiments disclosed herein. As used herein, the term “solvate”refers to an aggregate that comprises one or more molecules of acompound described herein with one or more molecules of solvent. Thesolvent may be water, in which case the solvate may be a hydrate.Alternatively, the solvent may be an organic solvent. Thus, thecompounds of the present invention may exist as a hydrate, including amonohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate,tetrahydrate and the like, as well as the corresponding solvated forms.The compounds described herein may be true solvates, while in othercases, the compound described herein may merely retain adventitiouswater or be a mixture of water plus some adventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compounddescribed herein and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Effective amount” or “therapeutically effective amount” refers to anamount of a compound according to the invention, which when administeredto a patient in need thereof, is sufficient to effect treatment fordisease-states, conditions, or disorders for which the compounds haveutility. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound according to theinvention which constitutes a therapeutically effective amount will varydepending on such factors as the compound and its biological activity,the composition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of the treatment, the type of disease-state or disorder beingtreated and its severity, drugs used in combination with orcoincidentally with the compounds described herein, and the age, bodyweight, general health, sex and diet of the patient. Such atherapeutically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, thestate of the art, and this disclosure.

The term “treatment” as used herein is intended to mean theadministration of a compound or composition according to the presentinvention to alleviate or eliminate symptoms of HIV infection and/or toreduce viral load in a patient. The term “treatment” also encompassesthe administration of a compound or composition according to the presentinvention post-exposure of the individual to the virus but before theappearance of symptoms of the disease, and/or prior to the detection ofthe virus in the blood, to prevent the appearance of symptoms of thedisease and/or to prevent the virus from reaching detectible levels inthe blood, and the administration of a compound or composition accordingto the present invention to prevent perinatal transmission of HIV frommother to baby, by administration to the mother before giving birth andto the child within the first days of life.

The term “antiviral agent” as used herein is intended to mean an agent(compound or biological) that is effective to inhibit the formationand/or replication of a virus in a human being, including but notlimited to agents that interfere with either host or viral mechanismsnecessary for the formation and/or replication of a virus in a humanbeing.

The term “inhibitor of HIV replication” as used herein is intended tomean an agent capable of reducing or eliminating the ability of HIV toreplicate in a host cell, whether in vitro, ex vivo or in vivo.

The compounds described herein, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

An “enantioenriched” compound refers to a compound which contains morethan 50% of one of a pair of enantiomers. An “enantioenriched” compoundmay have an enantiomeric excess (% ee) of over 5%, over 10%, over 20%,over 30%, over 40%, over 50%, over 60%, over 70%, over 80%, over 90%,over 95%, over 99%, or over 99.9%.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”. Also, the singular forms “a” and “the” include plural referencesunless the context clearly dictates otherwise. Thus, e.g., reference to“the compound” includes a plurality of such compounds and reference to“the assay” includes reference to one or more assays and equivalentsthereof known to those skilled in the art.

General Schemes

Certain embodiments are directed to the multistep general syntheticmethods described below, namely General Schemes I-VI. All substituentgroups in the steps described below are as defined as follows:

-   -   Hal is halogen,    -   n is 1, 2, or 3,    -   L is —C(R^(c))₂—, —C(R^(c))₂C(R^(c))₂—,        —C(R^(c))₂C(R^(c))₂C(R^(c))₂—, or        —C(R^(c))₂C(R^(c))₂C(R^(c))₂C(R^(c))₂—,    -   each R^(c) is, independently, hydrogen, halo, hydroxyl or        C₁-C₄alkyl,    -   each R^(a), R^(b), R^(d), R¹, and R² is, independently, alkyl,        aryl, or aralkyl.

In some embodiments, Hal is halogen, which may be the same or different.

In certain embodiments, each R^(a), R^(b), R^(d), R¹, and R² is,independently, (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or (C₂-C₁₀)aryl (C₁-C₄)alkyl.

In some embodiments, each R^(a), R^(b), R¹, and R² is, independently,(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl.

In certain embodiments, each R^(b) is, independently, (C₁-C₄)alkyl.

In certain embodiments, each R^(c) is, independently, hydrogen, —F, —Cl,hydroxyl, or methyl. In certain embodiments, each R^(c) is,independently, hydrogen, —F, or —Cl. In certain embodiments, each R^(c)is hydrogen.

In certain embodiments, each R^(a), R^(b), R^(d), R¹, and R² is,independently, methyl, ethyl, phenyl, or benzyl. In certain embodiments,each R^(a), R^(b), R¹, and R² is methyl. In particular embodiments,R^(d) is ethyl.

In certain embodiments, each R¹ is C₁-C₄alkyl and each R¹, togetheralong with the atoms to which they are bonded, forms a heterocycle. Incertain embodiments, each R¹ is methyl or ethyl, and each R¹, togetheralong with the atoms to which they are bonded, forms a heterocycle. Incertain embodiments, each R¹ is methyl, and each R¹, together along withthe atoms to which they are bonded, forms a heterocycle

General Scheme I:

In certain embodiments, a process according to general scheme I isprovided:

wherein the process comprises the following steps:

-   -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid and N-1, or salts or        co-crystals thereof, in the presence of a base to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I.

In some embodiments, N-1 is in the form of a salt or a co-crystal.

General Scheme II:

In certain embodiments, a process according to general scheme I isprovided:

wherein the process comprises the following steps:

-   -   reacting A-1 with H-1 in the presence of a catalyst, a base, and        an acylating reagent to yield B-1;    -   reacting B-1 with J-1 in the presence of an acid to yield C-1;    -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid and N-1 in the presence of a        base to yield G-1;    -   reacting G-1 under conditions suitable yield a compound of        Formula I.

In some embodiments, J-1 is in the form of a salt or a co-crystal.

In some embodiments, N-1 is in the form of a salt or a co-crystal.

General Scheme III:

In certain embodiments, a process according to general scheme I isprovided:

wherein the process comprises the following steps:

-   -   reacting B-1 with Q-1 to yield BB-1 reacting BB-1 with J-1 to        yield C-1;    -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid and N-1, or salts or        co-crystals thereof, in the presence of a base to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I.

In some embodiments, J-1 is in the form of a salt or a co-crystal.

General Scheme IV:

In certain embodiments, a process according to general scheme I isprovided:

wherein the process comprises the following steps:

-   -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with M-1 to yield EE-1;    -   reacting EE-1 with K-1 to yield F-1;    -   reacting F-1 with at least one acid and N-1, in the presence of        a base to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I.

In some embodiments, N-1 is in the form of a salt or a co-crystal.

General Scheme V

In certain embodiments, a process according to general scheme I isprovided:

wherein the process comprises the following steps:

-   -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with a base to yield a compound of Formula II.        General Scheme VI

In certain embodiments, a process according to general scheme I isprovided:

wherein the process comprises the following steps:

-   -   reacting B-1.J-1 under conditions suitable to yield C-1;    -   reacting C-1 with an alkylated formamide acetal to yield D-1;    -   reacting D-1 with K-1 to yield E-1;    -   reacting E-1 with M-1 in the presence of a base to yield F-1;    -   reacting F-1 with at least one acid to yield FF-1;    -   reacting FF-1 with N-1, or salts or co-crystals thereof, in the        presence of an additive to yield G-1;    -   reacting G-1 under conditions suitable to yield a compound of        Formula I.

In some embodiments reacting F-1 with at least one acid yields thefollowing aldehyde:

which is hydrated to give FF-1.

General Scheme VII

Certain embodiments are directed to the multistep synthetic methoddescribed below, namely General Scheme VII:

wherein the process comprises the following steps:

-   -   hydrogenating (−)-Vince lactam and protecting the reduced        product to yield a-1;    -   reacting a-1 with R³-M to yield b-1;    -   oxidizing b-1 and hydrolyzing the product of the oxidation to        yield c-1.

In General Scheme VII:

-   -   PG is a protecting group; and    -   R³M is a n-alkyl Grignard reagent or an alkyl organolithium        reagent.

In certain embodiments, the protecting group (PG) is selected from thegroup consisting of Boc, phtalimide, benzyl, FMoc, acetyl,triphenylmethyl, trifluoroacetyl, benzylidene, p-Toluenesulfonamide,p-Methoxybenzyl carbonyl, benzoyl, p-methoxybenzyl, carbamates,3,4-Dimethoxybenzyl, p-methoxyphenyl, sulfonamides and carbobenzyloxy.In particular embodiments, the protecting group is Boc.

In certain embodiments, R³M is an ethylmagnesium halide, ann-propylmagnesium halide, and n-butylmagnesium halide, methyl lithium,n-butyllithium, or n-hexyllithium. In particular embodiments, R³M ismethyl magnesium bromide.

Scheme VIII

Certain embodiments are directed to the multistep synthetic methoddescribed below, namely Scheme VIII:

wherein the process comprises the following steps:reacting g-1x under conditions effective to yield h-1x; andreacting h-1x under conditions effective to yield N-1x.

In some embodiments, the process further comprises the following step:

reacting f-1x under conditions effective to yield g-1x.

In some embodiments, g-1x is hydrogenated in the presence of a catalystand a source of hydrogen to yield h-1x.

In some embodiments, the catalyst is selected form the group consistingof palladium (Pd) based catalysts, PtO₂, Raney Nickel, RhCl(PPh₃)₃,Nyori's catalyst, and Crabtree's catalyst. Exemplary palladium catalystinclude Pd/C. In some embodiments, the catalyst is selected form thegroup consisting of Pd/C, PtO₂, Raney Nickel, RhCl(PPh₃)₃, Nyori'scatalyst, and Crabtree's catalyst. In some embodiments, the catalyst isPtO₂.

In certain embodiments, the source of hydrogen is formic acid,hydrazine, dihydronapthalene, dihydroanthracene, H₂ gas or Hantzch esterand isopropanol. In particular embodiments, the source of hydrogen is H₂gas. In particular embodiments, the source of hydrogen is H₂ gas underan atmosphere of hydrogen.

In some embodiments, h-1x is reacted with an acid to yield N-1x. In someembodiments, the acid is a sulfonic acid, including but not limited tomethanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid;an inorganic acid, including but not limited to phosphoric acid,hydrochloric acid and sulfuric acid; a carboxylic acid including but notlimited to trifluoroacetic acid, oxalic acid and benzoic acid. Incertain embodiments, the acid is an inorganic acid. In particularembodiments, the acid is hydrochloric acid. In particular embodiments,the acid is anhydrous hydrochloric acid.

In some embodiments, g-1x is

and N-1x is

In some embodiments, f-1x is

Scheme IX

Certain embodiments are directed to the multistep synthetic methoddescribed below, namely General Scheme IX:

wherein the process comprises the following steps:reacting racemic c-1a (which is a mixture of cc-1b and cc-1a) with anacyl donor and an enzyme to yield cc-1b and e-1;

isolating e-1 from cc-1b; and

hydrolyzing e-1 to yield enantioenriched cc-1a.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, CN, —NR^(z1)R^(z2), C(O)R^(z1),—C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —OC(O)NR^(z1)R^(z2),—NR^(z1)C(O)R^(z2), —NR^(z1)C(O)NR^(z2), —NR^(z1)C(O)OR^(z2), —SR^(z1),—S(O)₁₋₂R^(z1), —S(O)₂NR^(z1)R^(z2), —NR^(z1)S(O)₂R^(z2),NR^(z1)S(O)₂R^(z2), and OR^(z1).

In certain embodiments, R^(z1) and R^(z2) are independently selectedfrom the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, 3 to 12 membered heterocyclyl,C₆₋₁₀aryl and 5 to 10 membered heteroaryl.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, —C(O)OR^(z1) and R^(z1) isselected from the group consisting of H, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl,and 3 to 12 membered heterocyclyl.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, —C(O)OR^(z1) and R^(z1) isselected from the group consisting of H and C₁₋₆alkyl.

In certain embodiments, R^(x) is (C₁-C₄)alkyl-R^(y) and R^(y) isselected from the group consisting of H and CO₂H.

In certain embodiments, R^(x) is methyl or (CH₂)₃—CO₂H. In certainembodiments, R^(x) is (CH₂)₃—CO₂H.

In certain embodiments, the acyl donor is an anhydride or an ester. Incertain embodiments, the anhydride includes but is not limited toglutaric anhydride and acetic anhydride. In certain embodiments, theester includes but is not limited to vinyl acetate, isopropenyl acetate,4-chlorophenyl acetate and ethyl methoxy acetate. In particularembodiments, the acyl donor is glutaric anhydride.

In certain embodiments, the enzyme is a lipase. In certain embodiments,the lipase includes but is not limited to Novozyme 435, CAL-A, CAL-B,PPL, PSL-C, PSL, CRL and MML. In certain embodiments, the lipaseincludes but is not limited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL andMML. In certain embodiments, the enzyme is CAL-B. In certainembodiments, the enzyme is Novozyme 435.

Novozyme 435 is a CAL-B lipase immobilized on an hydrophobic carrier(acrylin resin).

CAL-B is Candida antartica B lipase.

CAL-A is Candida antartica A lipase.

PPL is Porcine Pancreas Lipase.

PSL is Pseudomonas cepacia lipase.

PSL-C is an immobilized lipase from Pseudomonas cepacia.

CRL is Candida rugosa lipase.

MML is Mucor miehei lipase.

Scheme X

Certain embodiments are directed to the multistep synthetic methoddescribed below, namely General Scheme X:

wherein the process comprises the following steps:reacting racemic c-1a (which is a mixture of cc-1b and cc-1a) with anacyl donor to yield racemic ee-1;reacting racemic ee-1 (which is a mixture of e-1 and e-2) with an enzymeto yield e-2 and cc-1a; andisolating enantioenriched cc-1a.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, CN, —NR^(z1)R^(z2), C(O)R^(z1),—C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —OC(O)NR^(z1)R^(z2),—NR^(z1)C(O)R^(z2), —NR^(z1)C(O)NR^(z2), —NR^(z1)C(O)OR^(z2), —SR^(z1),—S(O)₁₋₂R^(z1), —S(O)₂NR^(z1)R^(z2), —NR^(z1)S(O)₂R^(z2),NR^(z1)S(O)₂R^(z2), and OR^(z1).

In certain embodiments, each R^(z1) and R^(z2) is independently selectedfrom the group consisting of H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, 3 to 12 membered heterocyclyl,C₆₋₁₀aryl and 5 to 10 membered heteroaryl.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, —C(O)OR^(z1) and R^(z1) isselected from the group consisting of H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl,and 3 to 12 membered heterocyclyl.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, —C(O)OR^(z1) and R^(z1) isselected from the group consisting of H and C₁₋₆alkyl.

In certain embodiments, is (C₁-C₄)alkyl-R^(y) and R^(y) is selected fromthe group consisting of H and CO₂H.

In certain embodiments, R^(x) is methyl or (CH₂)₃—CO₂H. In certainembodiments, R^(x) is (CH₂)₃—CO₂H.

In certain embodiments, the acyl donor includes but is not limited to ananhydride or an acid chloride. In certain embodiments, the anhydrideincludes but is not limited to succinic anhydride and acetic anhydride.In certain embodiments, the acid chloride include but is not limited toacetyl chloride and benzoyl chloride. In particular embodiments, theacyl donor is Glutaric anhydride.

In certain embodiments, the enzyme is a lipase such as but are notlimited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In particularembodiments, the enzyme is CAL-B.

Scheme XI

Certain embodiments are directed to the multistep synthetic methoddescribed below, namely Scheme XI:

wherein the process comprises the following steps:reacting racemic c-1a (which is a mixture of cc-1b and cc-1a) with achiral acid to yield dd-1 and dd-2; andisolating enantioenriched dd-1.

In certain embodiments, the chiral acid is selected from the groupconsisting of:

-   -   single enantiomers of carboxylic acids including but not limited        to: naproxen, phenyl succinic acid, malic acid,        2-phenylpropionic acid, alpha-methoxyphenyl acetic acid,        tartranilic acid, 3-phenyllactic acid, α-hydroxyisovaleric acid,        2′-methoxy-tartranilic acid, (alpha-methylbenzyl)phthalamic        acid, 2′-chloro-tartranilic acid, pyroglutamic acid;    -   single enantiomers of mandelic acid derivatives including but        not limited to: mandelic acid, 2-chloromandelic acid,        4-bromo-mandelic acid, O-acetyl mandelic acid, 4-methyl-mandelic        acid;    -   single enantiomers of sulfonic acids including but not limited        to: camphor sulfonic acid;    -   single enantiomers of tartaric acid derivatives including but        not limited to: tartaric acid, dibenzoyl tartaric acid hydrate,        di-p-anisoyltartaric acid, di-toluyltartaric acid, dibenzoyl        tartaric acid hydrate;    -   single enantiomers of phosphoric acid derivatives including but        not limited to: phencyphos hydrate, chlocyphos, anisyphos, BINAP        phosphate; and    -   single enantiomers of amino acids including but not limited tos:        N-acetyl-phenylalanine, N-acetyl-leucine, N-acetyl-proline,        boc-phenylalanine, and boc-homophenylalanine.

In certain embodiments, the chiral acid is a single enantiomers of acarboxylic acid.

In particular embodiments, the acid is (R)-Naproxen. In particularembodiments, the acid is R-(+)-mandelic acid.

In particular embodiments, the acid is (S)-Naproxen. In particularembodiments, the acid is S-(+)-mandelic acid.

In certain embodiments, the reaction with the chiral acid occurs in asolvent selected from the group consisting of water, acetonitrile,ethanol, isopropanol, methyl ethyl ketone, isopropyl acetate, dioxane, amixture of water and a water-miscible organic solvents such as ethanoland isopropanol, an halogenated solvent such as dichloromethane andchloroform. In particular embodiments, the solvent is water orisopropanol or a mixture thereof. In particular embodiments, the solventis water. In particular embodiments, the solvent is isopropanol.

In certain embodiments, the reaction with the chiral acid is stirred at0 to 120° C., 20 to 120° C., 50 to 120° C., 80 to 120° C., or about 100°C. In certain embodiments, the reaction is stirred at about 20° C.

In certain embodiments, isolating dd-1 comprises selectivelyrecrystallizing dd-1. In certain embodiments, the recrystallizationoccurs in water, acetonitrile, ethanol, isopropanol, methyl ethylketone, isopropyl acetate, dioxane; a mixture of water andwater-miscible organic solvents such as ethanol and isopropanol, or ahalogenated solvent such as dichloromethane or chloroform. In certainembodiments, the recrystallization occurs in a mixture of methyl ethylketone and water.

In certain embodiments, dd-1 precipitates out of solution and isfiltered.

Schemes VII-XI disclose steps and intermediates which are useful for thethe preparation of N-1 and/or a compound of Formula I.

General Schemes—Individual Steps

Additional embodiments are directed to the individual steps of themultistep general synthetic methods described above, namely GeneralSchemes I-V and VI to XI. These individual steps and intermediates ofthe present invention are described in detail below. All substituentgroups in the steps described below are as defined in the multi-stepmethod above.

A. Acylation and Amidation of Meldrum's Acid to Provide C-1:

1. Conversion of A-1 to B-1

In particular embodiments, one equivalent of Meldrum's acid (A-1) and asuitable catalyst are suspended in a suitable solvent, and the resultingsolution is treated with about 1.2 equivalents of H-1. About 2equivalents of a suitable base are slowly added to the resultingsolution, followed by the addition of about 1.1 equivalents of asuitable acylating reagent. The reaction occurs at about 20 to 80° C.and is allowed to continue until consumption of Meldrum's acid iscomplete, as monitored by any suitable method known in the art.

In certain embodiments, the catalyst is a nucleophilic amine-containingcompound, such as, but is not limited to, 4-dimethylaminopyridine,imidazole, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, or pyridine. In further embodiments,the catalyst is a nucleophilic phosphine containing compound, such as,but not limited to, triphenylphosphine. In a particular embodiment, thecatalyst is 4-dimethylaminopyridine.

In certain embodiments, the solvent for the above reaction is a polarnon-protic solvent or an aromatic solvent. In certain embodiments, thesolvent for the above reaction is a polar non-protic solvent. In certainembodiments, the solvent for the above reaction is an aromatic solvent.Exemplary polar non-protic solvents include, but are not limited to,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,or N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the abovereaction include, but not limited to, pyridine, toluene, xylene,benzene, or chlorobenzene. In still further embodiments, the solvent isa mixture comprising at least one of the forgoing solvents. For example,in certain embodiments, the solvent is a mixture of up to three, or upto two, polar non-protic solvents selected from the group consisting ofacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,and N-methyl-2-pyrrolidinone. In other embodiments, the solvent is amixture of up to three, or up to two, aromatic solvents selected fromthe group consisting of pyridine, toluene, xylene, benzene, andchlorobenzene. In one embodiment the solvent is a mixture of up tothree, or up to two, solvents selected from the group consisting ofacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene, andchlorobenzene. In a further embodiment, the solvent is acetonitrile.

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R^(a) is(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certainembodiments, R^(a) is (C₁-C₄)alkyl. In certain embodiments R^(a) is—CH₃, that is H-1 is methoxyacetic acid.

In certain embodiments, the base is an amine base, an aromatic base,inorganic carbonate, a metal hydride, an alkoxide, or mixtures thereof.In certain embodiments, the base is an amine base. In certainembodiments, the base is an aromatic base. In certain embodiments, thebase is an inorganic carbonate. In certain embodiments, the base is ametal hydride. In certain embodiments, the base is an alkoxide.Exemplary amine bases include, but are not limited to, triethylamine,N,N-diisopropylethylamine, quinuclidine, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, tripropylamine, and tributylamine.Exemplary aromatic amine bases include, but are not limited to,pyridine. Exemplary inorganic carbonates include, but are not limitedto, lithium carbonate, sodium carbonate, potassium carbonate, or cesiumcarbonate. Exemplary metal hydrides, include, but are not limited to,sodium hydride or potassium hydride. Exemplary alkoxides include, butare not limited to, sodium methoxide, sodium tert-butoxide or lithiumtert-butoxide. In still further embodiments, the base is a mixturecomprising at least one of the preceding bases. For example, in certainembodiments, the base is a mixture of up to three, or up to two, aminebases. In certain embodiments, the base is a mixture of up to three, orup to two, aromatic bases. In certain embodiments, the base is a mixtureof up to three, or up to two, inorganic carbonates. In certainembodiments, the base is a mixture of up to three, or up to two, metalhydrides. In certain embodiments, the base is a mixture of up to three,or up to two, alkoxides. In certain embodiments, the base is a mixtureof up to three, or up to two, bases from the group consisting oftriethylamine, N,N-diisopropylethylamine, quinuclidine,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,tripropylamine, tributylamine, pyridine, lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydride,potassium hydride, sodium methoxide, sodium tert-butoxide and lithiumtert-butoxide. In a particular embodiment, the base is triethylamine.

In certain embodiments, the acylating reagent is a carboxylic acidactivating reagent, a carbodiimide derivative, or a mixture thereof. Incertain embodiments, the acylating reagent is a carboxylic acidactivating reagent. In certain embodiments, the acylating reagent is acarbodiimide derivative. In certain embodiments, the acylating reagentis a mixture of a carboxylic acid activating reagent and a carbodiimidederivative. Exemplary carboxylic acid activating reagents include,without limitation, pivaloyl chloride, carbonyldiimidazole, thionylchloride, and oxalyl chloride. Exemplary carbodiimide derivativesinclude, without limitation, carbonyldiimidazole andN,N′-dicyclohexylcarbodiimide. In certain embodiments, the acylatingreagent is pivaloyl chloride, carbonyldiimidazole, thionyl chloride,oxalyl chloride, or N,N′-dicyclohexylcarbodiimide. In certainembodiments, the acylating reagent is a mixture of up to three, or up totwo, reagents from the groups consisting of pivaloyl chloride,carbonyldiimidazole, thionyl chloride, oxalyl chloride, orN,N′-dicyclohexylcarbodiimide. In certain embodiments, the acylatingreagent is pivaloyl chloride. In certain embodiments, the reactionoccurs at about 20 to 70° C., about 20 to 60° C., about 20 to 50° C.,about 20 to 40° C., about 20 to 30° C., about 30 to 80° C., about 30 to70° C., about 30 to 60° C., about 30 to 50° C., about 30 to 40° C.,about 40 to 80° C., about 40 to 70° C., about 40 to 60° C., about 40 to50° C., about 50 to 80° C., about 50 to 70° C., about 50 to 60° C.,about 60 to 80° C., about 60 to 70° C., about 70 to 80° C., or anysubrange therebetween. In particular embodiments, the reaction occurs atabout 35 to 40° C., about 40 to 45° C., about 45 to 50° C., or anysubrange therebetween.

In particular embodiments, the catalyst is 4-dimethylaminopyridine, thesolvent is acetonitrile, R^(a) is —CH₃, the base is triethylamine, theacylating reagent is pivaloyl chloride and the reaction occurs at about45 to 50° C.

2. Conversion of B-1 to C-1

In a separate vessel, about 1.2 equivalents of J-1 is suspended in asuitable solvent. The resulting solution is treated with about 1.5equivalents of a suitable acid, and then this acidic solution is addedto the above acylation reaction in progress. The reaction is allowed tocontinue for about 12 to about 24 hours at about 20 to 80° C., afterwhich time the solvent is removed and C-1 is recovered and purified fromthe residue using any suitable technique known in the art, such as, butnot limited to solvent extraction, silica gel chromatography andcrystallization.

In certain embodiments, J-1 is suspended in a polar non-protic solventor an aromatic solvent. In certain embodiments, J-1 is suspended in apolar non-protic solvent. In certain embodiments, J-1 is suspended in anaromatic solvent. Exemplary polar non-protic solvent include, but arenot limited to, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidinone.Exemplary aromatic solvents include, but are not limited to, pyridine,toluene, xylene, benzene, and chlorobenzene. In still furtherembodiments, J-1 is suspended in a solvent mixture comprising one ormore polar non-protic solvents and/or one or more aromatic solvents. Incertain embodiments, J-1 is suspended in a solvent mixture comprising upto three, or up to two, polar non-protic solvents. In certainembodiments, J-1 is suspended in a solvent mixture comprising up tothree, or up to two, aromatic solvents. In certain embodiments, J-1 issuspended in a solvent mixture comprising up to three, or up to two,solvents from the group consisting of acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene, andchlorobenzene. In a further embodiment, J-1 is suspended inacetonitrile.

In particular embodiments, the acid is an inorganic acid, an organicacid, or a halogenated organic acid. In certain embodiments, the acid isan inorganic acid. In certain embodiments, the acid is an organic acid.Exemplary inorganic acids, include, but are not limited to hydrochloricacid, hydrobromic acid, and hydroiodic acid. Exemplary organic acids,include, but are not limited to, formic acid and acetic acid. In yetother embodiments the organic acid is a halogenated organic acid.Exemplary halogenated organic acids include, but are not limited to,trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroaceticacid, and perfluoropropionic acid. In still further embodiments, theacid is a mixture comprising one or more organic acids and one or moreinorganic acids. In certain embodiments, the acid is a mixturecomprising up to three, or up to two, organic acids. In certainembodiments, the acid is a mixture comprising up to three, or up to two,halogenated organic acids. In certain embodiments, the acid is a mixturecomprising up to three, or up to two, inorganic acids. In a certainembodiment, the acid is a mixture of up to three, or up to two, acidsselected from the group consisting of hydrochloric acid, hydrobromicacid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid,trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid.In a particular embodiment, the acid is trifluoroacetic acid.

In particular embodiments, each Hal is independently —F or —Cl. In aparticular embodiment, Hal is —F In certain embodiments, n=1-3. Incertain embodiments, n=2. In certain embodiments, n=3. In furtherembodiments, J-1 is

In certain embodiments, J-1 is

In further embodiments, J-1 is

In still further embodiments, J-1 is in the form of a salt orco-crystal, such as, but not limited to a salt or co-crystal ofhydrochloric acid or trifluoroacetic acid. In certain embodiments, J-1is a salt or co-crystal of methane sulfonic acid.

For example, in certain embodiments, J-1 is:

In a particular embodiment, J-1 is

In a particular embodiment, J-1 is

For example, in certain embodiments, J-1 is:

In a particular embodiment, J-1 is

In a particular embodiment, J-1 is

In certain embodiments, the reaction occurs at about 20 to 70° C., about20 to 60° C., about 20 to 50° C., about 20 to 40° C., about 20 to 30°C., about 30 to 80° C., about 30 to 70° C., about 30 to 60° C., about 30to 50° C., about 30 to 40° C., about 40 to 80° C., about 40 to 70° C.,about 40 to 60° C., about 40 to 50° C., about 50 to 80° C., about 50 to70° C., about 50 to 60° C., about 60 to 80° C., about 60 to 70° C.,about 70 to 80° C., or any subrange therebetween. In particularembodiments, the reaction occurs at about 35 to 40° C., about 40 to 45°C., about 45 to 50° C., or any subrange therebetween.

In certain embodiments, the solvent is removed under reduced pressure.In particular embodiments, C-1 is extracted from the crude residue bysolvent extraction. In a particular embodiment, the crude residue isdissolved in an organic solvent, such as ethyl acetate, and the organiclayer is washed with water. The combined aqueous layers are extractedwith an organic solvent, such as ethyl acetate. The combined organiclayers are washed with saturated sodium bicarbonate solution, and thecombined bicarbonate washes are back extracted with an organic solventsuch as ethyl acetate. Total combined organic layers are dried over adrying agent, such as magnesium sulfate, filtered, and concentratedunder reduced pressure. The resulting crude material is purified usingany suitable technique, such as silica gel chromatography to yield C-1.

In particular embodiments, J-1 is suspended in acetonitrile, the acid istrifluoroacetic acid, J-1 is

and the reaction occurs at about 45 to 50° C.

3. Formation of C-1 Through B-1.J-1 Salt

Alternatively, in certain embodiments, C-1 is formed via formation of aB-1.J-1 salt following the procedure below.

a. Formation of B-1.J-1 Salt by Addition of J-1 to B-1

The free acid of B-1 (about 1 equivalent) is dissolved in a solvent,followed by addition of J-1 (about 1 to about 5 equivalents). In certainembodiments, the salt is aged for up to 12 hours, up to 10 hours, up to8 hours, up to 6 hours, up to 4 hours, or up to 3 hours. The salt isobtained by any suitable methods known in the art, including but notlimited to solvent filtration, extraction, crystallization, and silicagel chromatography.

In certain embodiments, the solvent for the above reaction is a polarnon-protic solvent or an aromatic solvent. In certain embodiments, thesolvent for the above reaction is a polar non-protic solvent. In certainembodiments, the solvent for the above reaction is an aromatic solvent.Exemplary polar non-protic solvents include, but are not limited to,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,or N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the abovereaction include, but not limited to, pyridine, toluene, xylene,benzene, or chlorobenzene. In still further embodiments, the solvent isa mixture comprising at least one of the forgoing solvents. For example,in certain embodiments, the solvent is a mixture of up to three, or upto two, polar non-protic solvents selected from the group consisting ofacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,and N-methyl-2-pyrrolidinone. In other embodiments, the solvent is amixture of up to three, or up to two, aromatic solvents selected fromthe group consisting of pyridine, toluene, xylene, benzene, andchlorobenzene. In one embodiment the solvent is a mixture of up tothree, or up to two, solvents selected from the group consisting ofacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene, andchlorobenzene. In a further embodiment, the solvent is acetonitrile.

In some embodiments, B-1.J-1 is:

In certain embodiments, the reaction is stirred to about 15 to 30° C.,about 20 to 70° C., about 20 to 60° C., about 20 to 50° C., about 20 to40° C., about 20 to 30° C., about 30 to 80° C., about 30 to 70° C.,about 30 to 60° C., about 30 to 50° C., about 30 to 40° C., about 40 to80° C., about 40 to 70° C., about 40 to 60° C., about 40 to 50° C.,about 50 to 80° C., about 50 to 70° C., about 50 to 60° C., about 60 to80° C., about 60 to 70° C., about 70 to 80° C., or any subrangetherebetween. In further embodiments, the reaction proceeds at about 15to about 25° C.

In certain embodiments, the solvent is acetonitrile and the reactionproceeds at about 18 to about 25° C.

b. Formation of C-1 from salt B-1.J-1

The salt B-1.J-1 (about 1 equivalent) is suspended in a suitablesolvent. The resulting solution is treated with about 0.1 to 1equivalents of a suitable acid. The reaction is allowed to continue forabout 12 to about 24 hours at about 20 to 80° C., after which time thesolvent is removed and C-1 is recovered and purified from the residueusing any suitable technique known in the art, such as, but not limitedto solvent extraction, silica gel chromatography, crystallization, andfiltration.

In certain embodiments, the solvent for the above reaction is a polarnon-protic solvent or an aromatic solvent. In certain embodiments, thesolvent for the above reaction is a polar non-protic solvent. In certainembodiments, the solvent for the above reaction is an aromatic solvent.Exemplary polar non-protic solvents include, but are not limited to,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,or N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the abovereaction include, but not limited to, pyridine, toluene, xylene,benzene, or chlorobenzene. In still further embodiments, the solvent isa mixture comprising at least one of the forgoing solvents. For example,in certain embodiments, the solvent is a mixture of up to three, or upto two, polar non-protic solvents selected from the group consisting ofacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,and N-methyl-2-pyrrolidinone. In other embodiments, the solvent is amixture of up to three, or up to two, aromatic solvents selected fromthe group consisting of pyridine, toluene, xylene, benzene, andchlorobenzene. In one embodiment the solvent is a mixture of up tothree, or up to two, solvents selected from the group consisting ofacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene, andchlorobenzene. In a further embodiment, the solvent is acetonitrile.

In particular embodiments, the acid is an inorganic acid, an organicacid, or a halogenated organic acid. In certain embodiments, the acid isan inorganic acid. In certain embodiments, the acid is an organic acid.Exemplary inorganic acids, include, but are not limited to hydrochloricacid, hydrobromic acid, hydroiodic acid. Exemplary organic acids,include, but are not limited to, formic acid and acetic acid. In yetother embodiments the organic acid is a halogenated organic acid.Exemplary halogenated organic acids include, but are not limited to,trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroaceticacid, and perfluoropropionic acid. In certain embodiments, the acid istrifluoroacetic acid. In still further embodiments, the acid is amixture comprising one or more organic acids and one or more inorganicacids. In certain embodiments, the acid is a mixture comprising up tothree, or up to two, organic acids. In certain embodiments, the acid isa mixture comprising up to three, or up to two, halogenated organicacids. In certain embodiments, the acid is a mixture comprising up tothree, or up to two, inorganic acids. In a certain embodiment, the acidis a mixture of up to three, or up to two, acids selected from the groupconsisting of hydrochloric acid, hydrobromic acid, hydroiodic acid,formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid,trichloroacetic acid, and perfluoropropionic acid. In a particularembodiment, the acid is trifluoroacetic acid.

In certain embodiments, after the addition is complete the reaction isheated to about 20 to 70° C., about 20 to 60° C., about 20 to 50° C.,about 20 to 40° C., about 20 to 30° C., about 30 to 80° C., about 30 to70° C., about 30 to 60° C., about 30 to 50° C., about 30 to 40° C.,about 40 to 80° C., about 40 to 70° C., about 40 to 60° C., about 40 to50° C., about 50 to 80° C., about 50 to 70° C., about 50 to 60° C.,about 60 to 80° C., about 60 to 70° C., about 70 to 80° C., or anysubrange therebetween. In further embodiments, the reaction proceeds atabout 60° C.

In particular embodiments, the solvent is acetonitrile, the acid istrifluoroacetic acid and the reaction proceeds at about 60° C.

B. Alkylation of C-1 to Form E-1:

A solution of about one equivalent of C-1 in a suitable solvent istreated with about one to one and a half equivalents of an alkylatedformamide acetal and is stirred at about 0 to 60° C. for about 10 hoursto about 18 hours. The reaction is treated with about one equivalent ofK-1, and is allowed to continue for about one to about four hours, andis then quenched via the addition of an acid. E-1 is then extracted andpurified by any suitable methods known in the art, including but notlimited to solvent extraction, crystallization, and silica gelchromatography.

In a particular embodiment, the solvent is a non-protic polar organicsolvent such as, but not limited to, 2-methyl tetrahydrofuran,tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butylether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, or mixtures thereof. In a further embodiment,the solvent is 2-methyl tetrahydrofuran.

In certain embodiments, the alkylated formamide acetal is selected fromthe group consisting of N,N-dimethylformamide dimethyl acetal,N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropylacetal, N,N-diethylformamide dimethyl acetal, andN,N-diisopropylformamide dimethyl acetal. In a particular embodiment,the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In particular embodiments, one equivalent of C-1 is treated with about1.1 equivalents of the alkylated formamide acetal.

In certain embodiments, R¹ is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R¹ is (C₁-C₄)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R¹is C₁-C₄alkyl. In further embodiments R¹ is —CH₃, that is, K-1 isaminoacetaldehyde dimethyl acetal.

In certain embodiments, the reaction is quenched with an inorganic acid,an organic acid, or a halogenated organic acid. In certain embodiments,the acid is an inorganic acid. In certain embodiments, the acid is anorganic acid. In certain embodiments, the acid is a halogenated organicacid. Exemplary inorganic acids, include, but are not limited tohydrochloric acid, hydrobromic acid, hydroiodic acid. Exemplary organicacids, include, but are not limited to, formic acid and acetic acid.Exemplary halogenated organic acids include, but are not limited to,trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroaceticacid, and perfluoropropionic acid. In still further embodiments, theacid is a mixture comprising one or more organic acids, one or moreinorganic acids, and/or one or more halogenated organic acids. Incertain embodiments, the acid is a mixture comprising up to three, or upto two, organic acids. In certain embodiments, the acid is a mixturecomprising up to three, or up to two, halogenated organic acids. Incertain embodiments, the acid is a mixture comprising up to three, or upto two, inorganic acids. In a certain embodiment, the acid is a mixtureof up to three, or up to two, acids selected from the group consistingof hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid,trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroaceticacid, and perfluoropropionic acid. In a particular embodiment, the acidis trifluoroacetic acid. In particular embodiments, the reaction isquenched with hydrochloric acid. In particular embodiments, the reactionis quenched with 2 N HCl. In certain embodiments, the reaction is notquenched.

In certain embodiments, the reaction proceeds at about 10 to 60° C.,about 10 to 50° C., about 10 to 40° C., about 10 to 30° C., about 10 to20° C., 20 to 60° C., about 20 to 50° C., about 20 to 40° C., about 20to 30° C., about 30 to 60° C., about 30 to 50° C., about 30 to 40° C.,about 40 to 60° C., about 40 to 50° C., about 50 to 60° C., or anysubrange therebetween. In particular embodiments, the reaction proceedsat room temperature. In further embodiments, the reaction proceeds atabout 15 to about 25° C.

In particular embodiments, the solvent is 2-methyl tetrahydrofuran, thealkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, R¹is —CH₃, and the reaction proceeds at about 18 to about 23° C.

C. Cyclization of E-1 to Form F-1:

In particular embodiments, a solution of about one equivalent of E-1 andabout one to five equivalents of M-1 in a first suitable solvent iscombined and cooled to about 0 to 5° C. In certain embodiments, the baseis slowly introduced to the reaction mixture while the internaltemperature of the reaction is kept cool throughout the addition (e.g.,below room temperature, or below about 25° C., or below about 20° C., orbelow about 15° C.). After the addition is complete the reaction isheated to about 20 to 80° C. for at least about 14 hours.

After this time has elapsed, the reaction may be diluted with an aqueousacidic solution and a further suitable organic solvent and the productextracted and purified by any suitable methods known in the art,including but not limited to solvent extraction, crystallization, andsilica gel chromatography. In certain embodiments, the aqueous acidicsolution is hydrochloric acid and acetic acid. For example, in certainembodiments, the aqueous acidic solution is glacial acetic acid.

In particular embodiments, the first solvent is one or more alcohols,one or more polar organic solvents, or a mixture of or more alcohols andone or more polar organic solvents. In certain embodiments, the firstsolvent is up to three alcohols, up to three polar organic solvents, ora mixture thereof (i.e., a mixture of up to three, or up to two,alcohols and up to three, or up to two, polar organic solvents). Incertain embodiments, the first solvent is one or two alcohols, one ortwo polar organic solvents, or a mixture thereof (i.e., a mixture of oneor two alcohols and one or two polar organic solvents). In certainembodiments, the first solvent is an alcohol. In certain embodiments,the first solvent is a polar organic solvent. Exemplary alcoholsinclude, but are not limited to, methanol, ethanol, n-propanol,2-propanol, butanol, and tert-butanol. Exemplary polar organic solventsinclude, but are not limited to, acetone, acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, andN-methyl-2-pyrrolidinone. In certain embodiments, the first solvent ismethanol, ethanol, n-propanol, 2-propanol, butanol, tert-butanolacetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,1,4-dioxane, or N-methyl-2-pyrrolidinone. In a certain embodiment, thefirst solvent is methanol.

In particular embodiments, the base is a metal hydride, an alkoxide, ora bis(trialkylsilyl) amide. In certain embodiments, the base is a metalhydride. In certain embodiments, the base is an alkoxide. In certainembodiments, the base is a bis(trialkylsilyl) amide. Exemplary metalhydrides include, but are not limited to lithium hydride, sodiumhydride, and potassium hydride. Exemplary alkoxides include, but are notlimited to, sodium methoxide, sodium tert-butoxide, sodium ethoxide,potassium tert-butoxide, potassium ethoxide, sodium tert-pentoxide, andlithium tert-butoxide. Exemplary bis(trialkylsilyl) amide bases include,but are not limited to lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. Instill further embodiments, the base is a mixture of at least one of theforegoing bases. In certain embodiments, the base is a mixture of up tothree, or up to two, metal hydrides. In certain embodiments, the base isa mixture of up to three, or up to two, alkoxides. In certainembodiments, the base is a mixture of up to three, or up to two, metalbis(trialkylsilyl) amides. In certain embodiments, the base is a mixtureof up to three, or up to two, of the following bases: lithium hydride,sodium hydride, potassium hydride, sodium methoxide, sodiumtert-butoxide, sodium ethoxide, potassium tert-butoxide, potassiumethoxide, sodium tert-pentoxide, lithium tert-butoxide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassiumbis(trimethylsilyl)amide. In particular embodiments, the base is sodiummethoxide.

In certain embodiments, R² is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R² is (C₁-C₄)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R²is C₁-C₄alkyl. In certain embodiments, R² is —CH₃.

In certain embodiments, after the addition is complete the reaction isheated to about 20 to 70° C., about 20 to 60° C., about 20 to 50° C.,about 20 to 40° C., about 20 to 30° C., about 30 to 80° C., about 30 to70° C., about 30 to 60° C., about 30 to 50° C., about 30 to 40° C.,about 40 to 80° C., about 40 to 70° C., about 40 to 60° C., about 40 to50° C., about 50 to 80° C., about 50 to 70° C., about 50 to 60° C.,about 60 to 80° C., about 60 to 70° C., about 70 to 80° C., or anysubrange therebetween.

In particular embodiments, the first solvent is an alcohol, the base isan alkoxide, after the addition is complete the reaction is heated toabout 40 to about 50° C. and R² is (C₁-C₄)alkyl.

In particular embodiments, the first solvent is methanol, the base issodium methoxide, after the addition is complete the reaction is heatedto about 40 to about 50° C. and R² is —CH₃.

D. Alkylation and Cyclization of C-1 to Form F-1:

In certain embodiments, about one equivalent of C-1 and about 1 to about5 equivalents of an alkylated formamide acetal are combined in areaction vessel, and reaction mixture is agitated for approximately 30minutes. In certain embodiments, about one equivalent of C-1 and about 1to about 3 equivalents of an alkylated formamide acetal are combined ina reaction vessel. A first suitable solvent and about one equivalent ofK-1 are added to the mixture, and the reaction is allowed to proceed forseveral hours, after which the first solvent is removed by any suitablemeans known in the art.

The resulting material is dissolved in a second suitable solvent andabout 1 to about 5 equivalents of M-1 is added. The reaction mixture iscooled to about 0° C. to about 5° C., and then about one and a half totwo equivalents of a base is slowly added to the reaction mixture. Theinternal temperature of the reaction is kept cool throughout theaddition (e.g., below room temperature, or below about 25° C., or belowabout 20° C., or below about 15° C.). After the addition is complete thereaction is heated to about 20 to 80° C. for about 8 to about 16 hours.

After this time has elapsed, the reaction is cooled to room temperature,quenched via the addition of an acid and diluted with the addition of anorganic solvent. The product, F-1, may then be extracted and purified byany suitable methods known in the art, including but not limited tosolvent extraction, crystallization and silica gel chromatography.

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R^(a) is(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certainembodiments, R^(a) is C₁-C₄alkyl. In certain embodiments, R^(a) is —CH₃.

In a particular embodiment, the first solvent is a non-protic polarorganic solvent such as, but not limited to, 2-methyl tetrahydrofuran,tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butylether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, or mixtures thereof. In a further embodiment,the first solvent is 2-methyl tetrahydrofuran.

In certain embodiments, the alkylated formamide acetal is selected fromthe group consisting of N,N-dimethylformamide dimethyl acetal,N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropylacetal, N,N-diethylformamide dimethyl acetal, andN,N-diisopropylformamide dimethyl acetal. In a particular embodiment,the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In certain embodiments, R¹ is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R¹ is (C₁-C₄)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R¹is C₁-C₄alkyl. In further embodiments R¹ is —CH₃, that is K-1 isaminoacetaldehyde dimethyl acetal.

In particular embodiments, the base is a metal hydride, abis(trialkylsilyl) amide base, or an alkoxide. In certain embodiments,the base is a metal hydride. In particular embodiments, the base is abis(trialkylsilyl) amide base. In particular embodiments, the base is analkoxide. Exemplary metal hydrides include, but are not limited tolithium hydride, sodium hydride, and potassium hydride. Exemplarybis(trialkylsilyl) amide bases include, but are not limited to lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassiumbis(trimethylsilyl)amide. Exemplary alkoxides include, but are notlimited to, sodium methoxide, sodium tert-butoxide, sodium ethoxide,potassium tert-butoxide, potassium ethoxide, sodium tert-pentoxide, andlithium tert-butoxide. In still further embodiments, the base is amixture of at least one of the foregoing bases. In certain embodiments,the base is a mixture of up to three, or up to two, metal hydrides. Incertain embodiments, the base is a mixture of up to three, or up to two,bis(trialkylsilyl) amide base. In certain embodiments, the base is amixture of up to three, or up to two, alkoxides. In certain embodiments,the base is a mixture of up to three, or up to two, bases selected fromthe group consisting of lithium hydride, sodium hydride, potassiumhydride, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodiummethoxide, sodium tert-butoxide, sodium ethoxide, potassiumtert-butoxide, potassium ethoxide, sodium tert-pentoxide, and lithiumtert-butoxide. In particular embodiments, the base is sodium methoxide.In particular embodiments, a solution of base in alcohol is added to thereaction. A suitable alcohol includes but is not limited to, methanol,ethanol, n-propanol, 2-propanol, butanol, or tert-butanol. In a certainembodiment, the base is sodium methoxide. In a certain embodiment, thebase is added as 30% solution of sodium methoxide in methanol.

In particular embodiments, the second solvent is an alcohol or a polarsolvent. In certain embodiments, the second solvent is an alcohol. Incertain embodiments, the second solvent is a polar solvent. Exemplaryalcohols include, but are not limited to, methanol, ethanol, n-propanol,2-propanol, butanol, and tert-butanol. Exemplary polar organic solventsinclude, but are not limited to, acetone, acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, orN-methyl-2-pyrrolidinone. In a certain embodiment, the second solvent ismethanol.

In certain embodiments, R² is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R² is (C₁-C₄)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R²is C₁-C₄alkyl. In certain embodiments, R² is —CH₃.

In certain embodiments, after the addition is complete the reaction isheated to about 20 to 70° C., about 20 to 60° C., about 20 to 50° C.,about 20 to 40° C., about 20 to 30° C., about 30 to 80° C., about 30 to70° C., about 30 to 60° C., about 30 to 50° C., about 30 to 40° C.,about 40 to 80° C., about 40 to 70° C., about 40 to 60° C., about 40 to50° C., about 50 to 80° C., about 50 to 70° C., about 50 to 60° C.,about 60 to 80° C., about 60 to 70° C., about 70 to 80° C., or anysubrange therebetween.

In particular embodiments, R^(a) is (C₁-C₄)alkyl, the first solvent is2-methyl tetrahydrofuran, the alkylated formamide acetal isN,N-dimethylformamide dimethyl acetal, R¹ is (C₁-C₄)alkyl, the base isan alkoxide, the second solvent is an alcohol, after the addition iscomplete the reaction is heated to about 40 to about 50° C., and R² is(C₁-C₄)alkyl.

In particular embodiments, R^(a) is —CH₃, the first solvent is 2-methyltetrahydrofuran, the alkylated formamide acetal is N,N-dimethylformamidedimethyl acetal, R¹ is —CH₃, the base is sodium methoxide, the secondsolvent is methanol, after the addition is complete the reaction isheated to about 40 to about 50° C., and R² is —CH₃.

E. Preparation of EE-1 from D-1

D-1 is reacted with M-1 to yield EE-1. For example. D-1 is dissolved ina suitable solvent and about 1 to about 5 equivalents of M-1 is added.The reaction mixture is cooled to about 0° C. to about 5° C., and thenabout one and a half to two equivalents of a base is slowly added to thereaction mixture. The internal temperature of the reaction is kept coolthroughout the addition (e.g., below room temperature, or below about25° C., or below about 20° C., or below about 15° C.). After theaddition is complete the reaction is heated to about 20 to 80° C. forabout 8 to about 16 hours.

After this time has elapsed, the reaction is cooled to room temperature,quenched via the addition of an acid and diluted with the addition of anorganic solvent. The product, EE-1, may then be extracted and purifiedby any suitable methods known in the art, including but not limited tosolvent extraction, crystallization and silica gel chromatography.

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R^(a) is(C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certainembodiments, R^(a) is C₁-C₄alkyl. In particular embodiments, R^(a) is—CH₃.

In certain embodiments, R^(b) is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, In certainembodiments, each R^(b) is, independently (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R^(b) is C₁-C₄alkyl.In further embodiments R^(b) is —CH₃. In certain embodiments, In certainembodiments, each R^(b) is —CH₃.

In particular embodiments, the base is an inorganic carbonate, a metalhydride, or an alkoxide, or a mixture thereof. In particularembodiments, the base is an inorganic carbonate. In particularembodiments, the base is a metal hydride. In particular embodiments, thebase is an alkoxide. Exemplary inorganic carbonates include, withoutlimitation, lithium carbonate, sodium carbonate, potassium carbonate andcesium carbonate. Exemplary metal hydrides include, without limitation,sodium hydride and potassium hydride. Exemplary alkoxides include,without limitation, sodium methoxide, sodium tert-butoxide, sodiumethoxide, potassium tert-butoxide, potassium ethoxide, sodiumtert-pentoxide, and lithium tert-butoxide. In certain embodiments, thebase is a mixture of up to three, or in other embodiments, up to two,inorganic carbonates. In certain embodiments, the base is a mixture ofup to three, or in other embodiments, up to two, metal hydrides. Incertain embodiments, the base is a mixture of up to three, or in otherembodiments, up to two, alkoxides. In certain embodiments, the base is amixture of up to three, or in other embodiments, up to two, basesselected from the group consisting of lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydride,potassium hydride, sodium tert-butoxide, sodium ethoxide, potassiumtert-butoxide, potassium ethoxide, sodium tert-pentoxide, and lithiumtert-butoxide. In particular embodiments, the base is sodium methoxide.

In particular embodiments, the solvent is an alcohol or a polar solvent.In certain embodiments, the solvent is an alcohol. In certainembodiments, the solvent is a polar solvent. Exemplary alcohols include,but are not limited to, methanol, ethanol, n-propanol, 2-propanol,butanol, and tert-butanol. Exemplary polar organic solvents include, butare not limited to, acetone, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone. In acertain embodiment, the solvent is N-methyl-2-pyrrolidinone.

In certain embodiments, the reaction is quenched with an inorganic acid,an organic acid, or a halogenated organic acid. In certain embodiments,the acid is an inorganic acid. In certain embodiments, the acid is anorganic acid. In certain embodiments, the acid is a halogenated organicacid. Exemplary inorganic acids, include, but are not limited tohydrochloric acid, hydrobromic acid, hydroiodic acid. Exemplary organicacids, include, but are not limited to, formic acid and acetic acid.Exemplary halogenated organic acids include, but are not limited to,trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroaceticacid, and perfluoropropionic acid. In still further embodiments, theacid is a mixture comprising one or more organic acids, one or moreinorganic acids, and/or one or more halogenated organic acids. Incertain embodiments, the acid is a mixture comprising up to three, or upto two, organic acids. In certain embodiments, the acid is a mixturecomprising up to three, or up to two, halogenated organic acids. Incertain embodiments, the acid is a mixture comprising up to three, or upto two, inorganic acids. In a certain embodiment, the acid is a mixtureof up to three, or up to two, acids selected from the group consistingof hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid,trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroaceticacid, and perfluoropropionic acid. In a particular embodiment, the acidis trifluoroacetic acid. In particular embodiments, the reaction isquenched with hydrochloric acid. In particular embodiments, the reactionis quenched with 2 N HCl. In certain embodiments, the reaction is notquenched.

In certain embodiments, R² is (C₁-C₄)alkyl, (C₂-C₁₀)aryl, or(C₂-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R² is (C₁-C₄)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R²is C₁-C₄alkyl. In certain embodiments, R² is —CH₃.

In certain embodiments, after the addition is complete the reaction isheated to about 20 to 80° C., about 20 to 80° C., about 20 to 60° C.,about 20 to 50° C., about 20 to 40° C., about 20 to 30° C., about 30 to80° C., about 30 to 70° C., about 30 to 60° C., about 30 to 50° C.,about 30 to 40° C., about 40 to 80° C., about 40 to 70° C., about 40 to60° C., about 40 to 50° C., about 50 to 80° C., about 50 to 70° C.,about 50 to 60° C., about 60 to 80° C., about 60 to 70° C., about 70 to80° C., or any subrange therebetween.

In particular embodiments, R² is (C₁-C₄)alkyl, each R^(b) is(C₁-C₄)alkyl which are the same or different, R^(a) is (C₁-C₄)alkyl, thebase is an alkoxide, and the solvent is an organic solvent.

In particular embodiments, R² is —CH₃, each R^(b) is —CH₃, R^(a) is—CH₃, the base is sodium methoxide, and the solvent isN-methyl-2-pyrrolidinone.

F. Condensation of F-1 with N-1 to form G-1:

One equivalent of F-1 and a suitable solvent are combined in a reactionvessel, about 5 to 8 equivalents of a first acid and about 0.2 to about0.5 equivalent of a second acid are added. The reaction may take placebetween about 20 to about 100° C.

The reaction is allowed to continue for about 2 to about 5 hours, afterwhich about 1.5 equivalents of N-1 and about 2 to about 3 equivalents ofa base are slowly introduced to the reaction vessel. After the additionis completed, the reaction is allowed to progress for at least about 1hour.

Water and additional solvent are added to the reaction vessel and G-1 isextracted and purified by any suitable method known in the art,including but not limited to solvent extraction, silica gelchromatography and crystallization.

In particular embodiments, the solvent is a non-protic polar organicsolvent, such as, but not limited to, tetrahydrofuran, acetonitrile,diisopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide,N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone, ormixtures thereof. In certain embodiments, the solvent is a mixture ofone, two or three, or in certain embodiments, a mixture of one or two ofthe following solvents: tetrahydrofuran, acetonitrile, diisopropylether, methyl tert-butyl ether, N,N-dimethylformamide,N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone. Infurther embodiments, the solvent is acetonitrile.

In certain embodiments, the first acid is an organic acid, an organiccarboxylic acid, or an inorganic acid. In certain embodiments, the firstacid is an organic acid. In certain embodiments, the first acid is anorganic carboxylic acid. In certain embodiments, the first acid is aninorganic acid. Exemplary organic acids include, but are not limited tomethane sulfonic acid, trifluoromethanesulfonic acid and trifluoroaceticacid. Exemplary organic carboxylic acids include, but are not limited toacetic acid, formic acid, butyric acid, propionic acid, and benzoicacid. Exemplary inorganic acids include, but are not limited to,hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, orsulfuric acid. In yet further embodiments, the first acid is aceticacid.

In certain embodiments, the second acid is an organic acid, an organiccarboxylic acid, or an inorganic acid. In certain embodiments, thesecond acid is an organic acid. In certain embodiments, the second acidis an organic carboxylic acid. In certain embodiments, the first acid isan inorganic acid. Exemplary organic acids include, but are not limitedto methanesulfonic acid, trifluoromethanesulfonic acid andtrifluoroacetic acid. Exemplary inorganic acids include, but are notlimited to, hydrochloric acid, hydrobromic acid, and sulfuric acid.Exemplary organic carboxylic acids include, but are not limited toacetic acid, formic acid, butyric acid, propionic acid, or benzoic acid.In particular embodiments, the second acid is methanesulfonic acid orformic acid.

In certain embodiments, the first acid is acetic acid and the secondacid is methanesulfonic acid.

In certain embodiments, the first acid and the second acid are the sameacid. In yet other embodiments, the first acid and the second acid areformic acid or acetic acid.

In certain embodiments, N-1 is in solution when added to the reactionmixture.

In further embodiments, L is —CH₂—CH₂—, that is, N-1 is(1R,3S)-3-aminocyclopentan-1-ol:

In some embodiments, N-1 is

In particular embodiments, N-1 is a salt or co-crystal. Suitable saltsor co-crystals of N-1 include, but are not limited to, oxalic acid,hydrochloric acid, mandelic acid, R-mandelic acid, and S-mandelic acid.Suitable salts or co-crystals of N-1 include, but are not limited to,benzoic acid, naproxen, S-naproxen and R-naproxen.

In still further embodiments, N-1 is

In still further embodiments, N-1 is;

In certain embodiments, after the addition of the acid(s) the reactionis kept at about 20 to about 90° C., about 20 to about 80° C., about 20to about 70° C., about 20 to about 60° C., about 20 to about 50° C.,about 20 to about 40° C., about 20 to about 30° C., about 30 to about100° C., about 30 to about 90° C., about 30 to about 80° C., about 30 toabout 70° C., about 30 to about 60° C., about 30 to about 50° C., about30 to about 40° C., about 40 to about 100° C., about 40 to about 90° C.,about 40 to about 80° C., about 40 to about 70° C., about 40 to about60° C., about 40 to about 50° C., about 50 to about 100° C., about 50 toabout 90° C., about 50 to about 80° C., about 50 to about 70° C., about50 to about 60° C., about 60 to about 100° C., about 60 to about 90° C.,about 60 to about 80° C., about 60 to about 70° C., about 70 to about80° C., or any subrange therebetween. In still further embodiments,after the addition of the acid(s) the reaction is kept at about 65 toabout 70° C., about 70 to about 75° C., about 75 to about 80° C., or anysubrange therebetween.

In particular embodiments, the solvent is acetonitrile, the first acidis an organic carboxylic acid, the second acid is an organic carboxylicacid, and after the addition of the acids the reaction is kept at about70 to about 75° C.

In particular embodiments, the solvent is acetonitrile, the first acidis acetic acid, the second acid is methanesulfonic acid, after theaddition of the acids the reaction is kept at about 70 to about 75° C.,and N-1 is

G. Deprotection of G-1 to Form a Compound of Formula I:

A reaction vessel is charged with approximately one equivalent of G-1and a suitable solvent. About two to three equivalents of a metal salt,a Lewis acid, or other reagent is added to the solution. The resultingsuspension is stirred at about 40 to about 100° C. for about ten minutesto about three hours. The reaction is quenched by the addition of anacid and a compound of Formula I is then extracted and purified by anysuitable technique known in the art, such as, but not limited to,solvent extraction, preparative HPLC and crystallization.

In a particular embodiment, the solvent is a non-protic polar organicsolvent such as, but not limited to, 2-methyl tetrahydrofuran,tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butylether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, or mixtures thereof. In a further embodiment,the solvent is acetonitrile.

In certain embodiments, G-1 is reacted with at least one reagentselected from the group consisting of metal salts, Lewis acids, sodiumethanethiolate, sodium hexamethyldisiloxane, trifluoroacetic acid, andcombinations thereof.

In further embodiments, the metal salt is selected from the groupconsisting of magnesium bromide, lithium chloride, lithium bromide, andlithium iodide. In still further embodiments, the metal salt is lithiumchloride.

In particular embodiments, the Lewis acid is selected from the groupconsisting of boron trifluoride methyl etherate, boron trifluoridediethyl etherate, boron trifluoride dibutyl etherate, aluminiumchloride, aluminum bromide, boron trichloride, boron tribromide,chlorotrimethylsilane, iodotrimethylsilane, palladium, and borontrifluoride diethyl etherate. In certain embodiments, the Lewis acid isselected from the group consisting of chlorotrimethylsilane,iodotrimethylsilane, sodium ethanethiolate, sodium hexamethyldisiloxane,palladium, boron trifluoride diethyl etherate, and trifluoroacetic acid.

In particular embodiments, other reagents suitable to facilitate theconversion are sodium ethanethiolate, sodium hexamethyldisiloxane, andtrifluoroacetic acid

In particular embodiments, the deprotection of G-1 to form a compound ofFormula I takes place in the presence of about two to about threeequivalents of a reagent selected from the group consisting of:magnesium bromide, lithium chloride, lithium bromide, lithium iodide,boron trifluoride methyl etherate, boron trifluoride diethyl etherate,boron trifluoride dibutyl etherate, aluminium chloride, aluminumbromide, boron trichloride, boron tribromide, chlorotrimethylsilane,iodotrimethylsilane, palladium, boron trifluoride diethyl etherate,chlorotrimethylsilane, iodotrimethylsilane, sodium ethanethiolate,sodium hexamethyldisiloxane, palladium, boron trifluoride diethyletherate, and trifluoroacetic acid.

In certain embodiments, the reaction proceeds at about 40 to about 50°C., about 40 to about 60° C., about 40 to about 70° C., about 50 toabout 60° C., about 50 to about 70° C., about 50 to about 80° C., about60 to about 70° C., about 60 to about 80° C., or any subrangetherebetween. In particular embodiments, the reaction proceeds at about50° C.

In particular embodiments, the solvent is acetonitrile, the metal saltis magnesium bromide, and the reaction proceeds at about 50° C.

H. Hydrolysis of F-1 to Yield a Compound of Formula II:

A reaction vessel is charged with approximately one equivalent of F-1and a solution of about ten to fifteen parts of a first organic solventand about 3 to 8 parts water is prepared. About two equivalents of abase are added to the solution. The resulting suspension is stirred atabout 0 to about 50° C. for about 14 to about 17 hours. Conversion maybe monitored by any suitable method known in the art, such as, but notlimited to HPLC.

Water and a second organic solvent are added to the suspension and thepH adjusted to about pH 3 by the dropwise addition of a suitable acid.The product, a compound of Formula II, can then be extracted andoptionally purified by any suitable technique known in the art, such as,but not limited to, solvent extraction, silica gel chromatography andcrystallization.

In certain embodiments, the first organic solvent is an alcoholicsolvent or a polar organic solvent. In certain embodiments, the firstorganic solvent is an alcoholic solvent. In certain embodiments, thefirst organic solvent is a polar organic solvent. Exemplary alcoholicsolvents include, without limitation, methanol, ethanol, n-propanol,2-propanol, butanol, and tert-butanol. Exemplary polar organic solventsinclude, but are not limited to, N,N-dimethylformamide,N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidinone. Inparticular embodiments, the first organic solvent is methanol.

In further embodiments, the base is selected from the group consistingof lithium hydroxide, sodium hydroxide, potassium hydroxide, lithiumcarbonate, sodium carbonate and potassium carbonate. In still furtherembodiments, the base is lithium hydroxide monohydrate.

In certain embodiments, the reaction proceeds at about 10 to about 50°C., about 10 to about 40° C., about 10 to about 30° C., about 10 toabout 20° C., about 20 to about 50° C., about 20 to about 40° C., about20 to about 30° C., about 30 to about 50° C., about 30 to about 40° C.,about 40 to about 50° C., or any subrange therebetween. In particularembodiments, the reaction proceeds at room temperature. In furtherembodiments, the reaction proceeds at about 18 to about 23° C.

In particular embodiments, the base is lithium hydroxide monohydrate,the reaction proceeds at about 10 to about 50° C. and the first organicsolvent is methanol.

In particular embodiments, the base is lithium hydroxide monohydrate,the reaction proceeds at about 18 to about 23° C. and the first organicsolvent is methanol.

I. Preparation of BB-1 from B-1 and Q-1:

About one equivalent of B-1 and eight to twelve equivalents of Q-1 areadded to a reaction vessel and dissolved in a suitable organic solvent.The solution is then heated to about 85 to about 115° C. and allowed toproceed for about two to six hours, after which time the reaction iscooled to room temperature. BB-1 is then purified using techniques knownin the art, such as, but not limited to silica gel chromatography.

In certain embodiments, the solvent is a non-polar aromatic solvent or apolar aprotic solvent. In certain embodiments, the solvent is anon-polar aromatic solvent. In certain embodiments, the solvent is apolar aprotic solvent. Exemplary non-polar aromatic include, but are notlimited to, toluene, xylene, chlorobenzene, and dichlorobenzene.Exemplary polar aprotic solvents include, but are not limited to,N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, andN-methylpyrrolidinone. In still further embodiments, the reaction canoccur without additional solvent. In particular embodiments, the solventis toluene.

In certain embodiments, the reaction proceeds at about 85 to about 105°C., about 85 to about 95° C., about 95 to about 105° C., about 95 toabout 115° C., about 105 to about 115° C., about 100 to about 105° C.,about 105 to about 110° C., about 110 to about 115° C., or any subrangetherebetween.

In particular embodiments, the reaction proceeds at about 95 to about115° C., and the solvent is toluene.

In particular embodiments, the reaction proceeds at about 110 to about115° C., and the solvent is toluene.

J. Preparation of C-1 from BB-1:

About 1 equivalent of BB-1 and about 1 to about 3 equivalents of J-1 arecombined in a reaction vessel. The compounds are dissolved in a polarnon-protic solvent or an aromatic solvent. In certain embodiments, thecompounds are dissolved is suspended in a polar non-protic solvent. Incertain embodiments, the compounds are dissolved in an aromatic solvent.Exemplary polar non-protic solvent include, but are not limited to,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,and N-methyl-2-pyrrolidinone. Exemplary aromatic solvents include, butare not limited to, pyridine, toluene, xylene, benzene, andchlorobenzene. In still further embodiments, the compounds are dissolvedin a solvent mixture comprising one or more polar non-protic solventsand/or one or more aromatic solvents. In certain embodiments, thecompounds are dissolved in a solvent mixture comprising up to three, orup to two, polar non-protic solvents. In certain embodiments, thecompounds are dissolved in a solvent mixture comprising up to three, orup to two, aromatic solvents. In certain embodiments, the compounds aredissolved in a solvent mixture comprising up to three, or up to two,solvents from the group consisting of acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene, andchlorobenzene. In a further embodiment the compounds are dissolved intoluene.

In particular embodiments, each Hal is independently —F or —Cl. In aparticular embodiment, Hal is —F In certain embodiments, n=1-3. Incertain embodiments, n=2. In certain embodiments, n=3. In furtherembodiments, J-1 is

In certain embodiments, J-1 is

In further embodiments, J-1 is

In still further embodiments, J-1 is in the form of a salt orco-crystal, such as, but not limited to a salt or co-crystal ofhydrochloric acid or trifluoroacetic acid. In certain embodiments, J-1is a salt or co-crystal of methane sulfonic acid.

In certain embodiments, the reaction proceeds at about 65 to about 115°C., about 75 to about 115° C., about 85 to about 115° C., about 95 toabout 115° C., about 105 to about 115° C., about 65 to about 70° C.,about 70 to about 80° C., about 80 to about 90° C., about 90 to about100° C., about 100 to about 110° C., about 110 to about 115° C., or anysubrange therebetween.

In certain embodiments, the solvent is removed under reduced pressure.In particular embodiments, C-1 is extracted from the crude residue bysolvent extraction. The resulting crude material is purified using anysuitable technique, such as silica gel chromatography or crystallizationto yield C-1.

In particular embodiments, the compounds are dissolved in an aromaticsolvent, J-1 is

and the reaction proceeds at about 65 to about 115° C.

In particular embodiments, the compounds are dissolved in toluene, J-1is

and the reaction proceeds at about 100 to about 110° C.

K. Preparation of C-1 from B-1.J-1

B-1.J-1, a solvent and an acid are combined in a reactor underconditions effective to produce C-1.

In certain embodiments, the acid is absent. In certain embodiments, theacid is a protic acid or a Lewis acid. In certain embodiments, proticacids include but are not limited to trifluoroacetic acid,trichloroacetic acid, dichloroacetic acid, chloroacetic acid, aceticacid, formic acid, hydrochloric acid, hydrobromic acid,para-toluenesulfonic acid and methane sulfonic acid. In certainembodiments, Lewis acids include but are not limited to zinc chloride,magnesium bromide, magnesium triflate, copper triflate, and scandiumtriflate. In particular embodiments, the acid is trifluoroacetic acid.

In certain embodiments, about 10 equivalents, about 5 equivalents, about1 equivalents, or about 0.1 equivalent of acid is used in the reactionof B-1.J-1 to form C-1.

In certain embodiments, the solvent is toluene, heptane, water,2-methyltetrahydrofuran, iso-propylacetate, N,N-dimethylformamide,N-methyl-2-pyrrolidinone, methyl-tert-butyl ether, dimethylsulfoxide,n-butanol, acetonitrile, acetone, or a mixture thereof. In a particularembodiment, the solvent is acetonitrile.

In certain embodiments, B-1.J-1 is at a concentration ranging from about2 to 40 mL/g, about 2 to 20 mL/g, about 5 to 15 mL/g. In a particularembodiment, B-1.J-1 is at a concentration of about 10 mL/g.

In certain embodiments, the reaction mixture is heated to a temperaturebetween about 20 and 110° C., about 30 and 90° C., about 40 and 80° C.,about 50 and 70° C., about 55 and 65° C., or about 58 and 61° C. In aparticular embodiment, the reaction mixture is heated to about 60° C.

In certain embodiments, other additives are added to the reaction. Incertain embodiments, the additives include but are not limited tolithium chloride, sodium chloride, and potassium chloride.

In certain embodiments, B-1.J-1 is charged to the reactor in a singleportion at about 20° C. followed by heating. In certain embodiments,B-1.J-1 is charged to the reactor in portions over 1 hour duringheating.

In certain embodiments, the reaction is heated for about 1 to 24 hours,for about 2 to 12 hours, or for about 3 to 6 hours. In a particularembodiment, the reaction is heated for about 2.5 hours.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, the reaction is cooled down and the reactorcontents are partially distilled.

In certain embodiments, the organic phase is washed at least once withan aqueous solution. In certain embodiments, the aqueous solutioncontains about 23% NaCl, about 1.5% H₂SO₄, and about 76% water. Incertain embodiments, the aqueous solution contains about 20% NaCl.

In certain embodiments, a solution of the product is seeded with seedsof C-1 which had been previously isolated. In certain embodiments, solidC-1 is isolated by filtration.

In particular embodiments, each Hal is independently —F or —Cl. In aparticular embodiment, each Hal is —F In certain embodiments, n=1-3. Incertain embodiments, n=2. In certain embodiments, n=3. In furtherembodiments, J-1 is

In certain embodiments, J-1 is

In further embodiments, J-1 is

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁C₄)alkyl. In certain embodiments, R^(a) is (C₁-C₄)alkyl.In certain embodiments, R^(a) is methyl.

In particular embodiments, R^(a) is (C₁-C₄)alkyl, the solvent isacetonitrile, the reaction mixture is heated to about 60° C., and J-1 is

In particular embodiments, R^(a) is methyl, the solvent is acetonitrile,the reaction mixture is heated to about 60° C., and J-1 is

L. Enamine Formation from C-1 to Provide D-1

To a solution of C-1 and an acid in a solvent, about 0.5 to about 1.5equivalent of an alkylated formamide acetal is added under conditionseffective to produce D-1.

In particular embodiments, one equivalent of C-1 is combined with about1.1 equivalents of the alkylated formamide acetal.

In certain embodiments, the alkylated formamide acetal is selected fromthe group consisting of N,N-dimethylformamide dimethyl acetal,N,N-dimethylformamide diethyl acetal, N, N-dimethylformamide diisopropylacetal, N, N-diethylformamide dimethyl acetal, andN,N-diisopropylformamide dimethyl acetal. In a particular embodiment,the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In certain embodiments, the solvent is dichloromethane, tetrahydrofuran,acetone, acetonitrile, ethyl acetate, isopropyl acetate, toluene,N,N-dimethylformamide, N,N-dimethylacetamide, 2-methyltetrahydrofuran orN-methyl-2-pyrrolidone. In a particular embodiment, the solvent is2-methyltetrahydrofuran.

In certain embodiments, the acid is an organic acid. In certainembodiments, the organic acid includes, but is not limited totrifluoroacetic acid, formic acid, acetic acid, sulfuric acid,trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid.In certain embodiments, the acid is a mixture comprising up to three, orup to two, organic acids. In a particular embodiment, the acid istrifluoroacetic acid.

In certain embodiments, the reaction mixture is heated to an internaltemperature of about 40° C. before adding the alkylated formamideacetal.

In certain embodiments, the reaction proceeds at about 0 to 75° C.,about 10 to 60° C., about 20 to 50° C., about 40 to 50° C., or about 30to 40° C. In particular embodiments, the reaction proceeds at roomtemperature. In further embodiments, the reaction proceeds at about 40°C.

In certain embodiments, the reaction proceeds for about 0.1 hours toabout 12 hours, for about 0.1 hours to about 6 hours, for about 0.1 hourto about 3 hours, for about 0.1 hour to about 1 hour, or for about 0.2hour to about 0.5 hour.

In certain embodiments, D-1 is extracted and purified by any suitablemethods known in the art, including but not limited to solventextraction, crystallization, and chromatography.

In certain embodiments, seeds of D-1 are added and the mixture isstirred. In certain embodiments, the mixture is stirred at about 40° C.for at least 1 hour.

In certain embodiments, about 0.2 to 0.6 equivalent of alkylatedformamide acetal is added and the reaction mixture is agitated for atleast about 25 minutes. The reaction mixture is cooled to roomtemperature and allowed to stir for about 12 hours.

In certain embodiments, the contents of the reactor are filtered, andthe filter cake is rinsed with a solvent and dried to yield D-1. Incertain embodiments, the solvent is a combination of2-methyltetrahydrofuran and heptanes.

In particular embodiments, each Hal is independently —F or —Cl. In aparticular embodiment, each Hal is —F In certain embodiments, n=1-3. Incertain embodiments, n=2. In certain embodiments, n=3.

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁C₄)alkyl. In certain embodiments, R^(a) is (C₁-C₄)alkyl.In certain embodiments, R^(a) is methyl.

In certain embodiments, each R^(b) is independently (C₁-C₄)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁C₄)alkyl. In certain embodiments, eachR^(b) is independently (C₁-C₄)alkyl. In certain embodiments, R^(b) ismethyl.

In particular embodiments, R^(b) is (C₁-C₄)alkyl, R^(a) is (C₁-C₄)alkyl,the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal,the solvent is 2-methyltetrahydrofuran, the reaction proceeds at about10 to about 60° C., the acid is trifluoroacetic acid, each Hal is —F andn=3.

In particular embodiments, R^(b) is methyl, R^(a) is methyl, thealkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, thesolvent is 2-methyltetrahydrofuran, the reaction proceeds at about 40°C., the acid is trifluoroacetic acid, Hal is —F and n=3.

M. Formation of F-1 from D-1 Through E-1

To a solution of D-1 in a solvent, is added about 1.1 equivalent of K-1under conditions effective to produce E-1.

In certain embodiments, the solvent is an alcoholic solvent such as, butnot limited to ethanol, n-propanol, 2-propanol, butanol, methanol andtert-butanol, or an aprotic polar organic solvents such as, but notlimited to 2-methyl tetrahydrofuran, tetrahydrofuran, acetone,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,and N-methyl-2-pyrrolidinone. In particular embodiments, the solvent ismethanol.

In certain embodiments, K-1 is an aminoacetaldehyde acetal such as, butnot limited to, aminoacetaldehyde diethylacetal, aminoacetaldehydedipropylacetal, Aminoacetaldehyde dimethylacetal, and aminoacetaldehydedibutalacetal. In certain embodiments, K-1 is aminoacetaldehydedimethylacetal.

In certain embodiments, the reaction proceeds at about 10 to 60° C.,about 10 to 50° C., about 10 to 40° C., about 10 to 30° C., about 10 to20° C., 20 to 60° C., about 20 to 50° C., about 20 to 40° C., about 20to 30° C., about 30 to 60° C., about 30 to 50° C., about 30 to 40° C.,about 40 to 60° C., about 40 to 50° C., about 50 to 60° C., or anysubrange therebetween. In particular embodiments, the reaction proceedsat room temperature. In further embodiments, the reaction proceeds atabout 16° C. to about 23° C.

In certain embodiments, the reaction is stirred for about 0.1 to about12 hours, about 0.5 to about 4 hours, about 1 to about 2 hours.

Once the reaction has progressed sufficiently to produce E-1, M-1 isadded to the reaction mixture.

In certain embodiments, about 1 to about 10 or about 1 to about 5equivalents of M-1 is added. In a particular embodiment, about 5equivalents of M-1 is added.

In certain embodiments, M-1 is dimethyl oxalate, diethyl oxalate,dipropyl oxalate, or dibutyl oxalate. In a particular embodiment, M-1 isdimethyl oxalate.

The reaction mixture is stirred at a temperature sufficient to achievedissolution of M-1. In certain embodiments, the reaction mixture isstirred at about 20-80° C., at about 20-70° C., at about 20-60° C., atabout 30-60° C., at about 40-50° C. or at about 45° C.

In certain embodiments, a base is added to the reaction mixturefollowing the addition of M-1.

In certain embodiments, the base is a metal hydride, an alkoxide, aninorganic carbonate, or a bis(trialkylsilyl) amide. In certainembodiments, the base is a metal hydride. In certain embodiments, thebase is an alkoxide. In certain embodiments, the base is an inorganiccarbonate. In certain embodiments, the base is a bis(trialkylsilyl)amide. Exemplary metal hydrides include, but are not limited to lithiumhydride, sodium hydride, and potassium hydride. Exemplary alkoxidesinclude, but are not limited to, sodium methoxide, sodium tert-butoxide,sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodiumtert-pentoxide, and lithium tert-butoxide. Exemplary bis(trialkylsilyl)amide bases include, but are not limited to lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassiumbis(trimethylsilyl)amide. Exemplary carbonates include, but are notlimited to lithium, sodium, potassium, and cesium carbonate.

In still further embodiments, the base is a mixture of at least one ofthe foregoing bases. In certain embodiments, the base is a mixture of upto three, or up to two, metal hydrides. In certain embodiments, the baseis a mixture of up to three, or up to two, alkoxides. In certainembodiments, the base is a mixture of up to three, or up to two, metalbis(trialkylsilyl) amides. In certain embodiments, the base is a mixtureof up to three, or up to two, of the following bases: lithium hydride,sodium hydride, potassium hydride, sodium methoxide, sodiumtert-butoxide, sodium ethoxide, potassium tert-butoxide, potassiumethoxide, sodium tert-pentoxide, lithium tert-butoxide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassiumbis(trimethylsilyl)amide.

In particular embodiments, the base is sodium methoxide. In particularembodiments, the base is sodium methoxide in solution in methanol.

In certain embodiments, after the addition of the base, the reaction isheated to about 20 to 80° C., 20 to 70° C., about 20 to 60° C., about 20to 50° C., about 20 to 40° C., about 20 to 30° C., about 30 to 80° C.,about 30 to 70° C., about 30 to 60° C., about 30 to 50° C., about 30 to40° C., about 40 to 80° C., about 40 to 70° C., about 40 to 60° C.,about 40 to 50° C., about 50 to 80° C., about 50 to 70° C., about 50 to60° C., about 60 to 80° C., about 60 to 70° C., about 70 to 80° C., orany subrange therebetween. In a particular embodiment, the reaction isheated to about 42 to 48° C. In a particular embodiment, the reaction isheated to about 45° C.

In certain embodiments, the reaction is stirred for about 1 to about 24hours, about 6 to about 24 hours, about 12 to about 20 hours, about 14to about 18 hours.

In certain embodiments, the reaction is diluted with an aqueous solutionand F-1 is extracted and purified by any suitable methods known in theart, including but not limited to solvent extraction, crystallization,and silica gel chromatography.

In certain embodiments, the temperature is reduced to about 34-37° C.over the course of about 1 hour, optionally charged with F-1 seedcrystals and allowed to age for about 1-2 hours. At this point, water isadded and temperature is reduced to about 18-22° C. over 1 hour. Theresulting slurry is filtered.

In certain embodiments, liquors are recycled to displace solidsremaining in the reactor. The collected solids on the filter are thenwashed with a 1:1 mixture of water and methanol, followed by water. Thecollected wet cake is dried in a vacuum oven at about 36-42° C. forabout 16 hours, providing F-1.

In certain embodiments, R¹ is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R¹ is C₁-C₄alkyl. Infurther embodiments R¹ is —CH₃, that is, K-1 is aminoacetaldehydedimethyl acetal.

In certain embodiments, R² is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₀-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R² is C₁-C₄alkyl. Incertain embodiments, R² is —CH₃.

In particular embodiments, each Hal is independently —F or —Cl. In aparticular embodiment, Hal is —F In certain embodiments, n=1-3. Incertain embodiments, n=2. In certain embodiments, n=3.

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁C₄)alkyl. In certain embodiments, R^(a) is (C₁-C₄)alkyl.In certain embodiments, R^(a) is methyl.

In certain embodiments, each R^(b) is independently (C₁-C₄)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁C₄)alkyl. In certain embodiments, eachR^(b) is independently (C₁-C₄)alkyl. In certain embodiments, R^(b) ismethyl.

In particular embodiments, R^(b) is methyl, R^(a) is (C₁-C₄)alkyl, eachHal is —F, n=3, R² is (C₁-C₄)alkyl, R¹ is (C₁-C₄)alkyl, the solvent isan alcoholic solvent, K-1 is aminoacetaldehyde dimethylacetal, the firstreaction proceeds at about 2 to about 40° C., the second reaction isheated to about 20 to about 80° C., the base is n alkoxide, and M-1 isdimethyl oxalate

In particular embodiments, R^(b) is methyl, R^(a) is methyl, Hal is —F,n=3, R² is —CH₃, R¹ is —CH₃, the solvent is methanol, K-1 isaminoacetaldehyde dimethylacetal, the first reaction proceeds at about16 to about 23° C., the second reaction is heated to about 45° C., thebase is sodium methoxide, and M-1 is dimethyl oxalate

N. Acetal Hydrolysis of F-1 to Form FF-1

To a solution of F-1 in a solvent, is added about 0.1 to 1 equivalent ofa first acid and about 2 to 20 equivalents of a second acid underconditions effective to produce FF-1.

In some embodiments, about 0.1 to 0.5 equivalent of the first acid isadded. In particular embodiments, about 0.1 equivalent of the first acidis added.

In some embodiments, the solvent is a polar organic solvent or a weakprotic acid. In some embodiments, the polar organic solvent include, butis not limited to propionitrile, tetrahydroduran, 1,4-dioxane,acetonitrile and ethyl acetate. In some embodiments, the weak proticacid include, but is not limited to formic acid, propionic acid andbutyric acid. In a particular embodiment, the solvent is acetonitrile.

In some embodiments, the first acid is a strong protic acid including,but not limited to methanesulfonic acid, sulfuric acid, hydrochloricacid, trifluoroacetic acid, p-Toluenesulfonic acid and camphorsulfonicacid.

In a particular embodiment, the first acid is p-Toluenesulfonic acid. Ina particular embodiment, the first acid is p-Toluenesulfonic acidmonohydrate.

In some embodiments, the second acid is a weak protic acid including,but not limited to acetic acid, formic acid, propionic acid and butyricacid. In a particular embodiment, the second acid is acetic acid.

The reaction is then heated to about 20 to 120° C., about 40 to 100° C.,about 60 to 80° C., or about 70 to 80° C. In a particular embodiment,the reaction is heated to about 75° C.

In certain embodiments, the reaction is stirred for about 1 to about 24hours, for about 4 to about 14 hours, for about 8 to about 10 hours.

In certain embodiments, water is added to the reaction mixture.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, the mixture is concentrated under reducedpressure to remove the solvent. The resultant slurry is then aged atroom temperature for about 2 hours, filtered and washed with water. Thecake is dried in a vacuum oven at 50° C. for at least 10 hours to giveFF-1.

In certain embodiments, R¹ is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R¹ is C₁-C₄alkyl. Infurther embodiments R¹ is —CH₃.

In certain embodiments, R² is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R² is C₁-C₄alkyl. Incertain embodiments, R² is —CH₃.

In particular embodiments, each Hal is independently —F or —Cl. In aparticular embodiment, Hal is —F In certain embodiments, n=1-3. Incertain embodiments, n=2. In certain embodiments, n=3.

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁C₄)alkyl. In certain embodiments, R^(a) is (C₁-C₄)alkyl.In certain embodiments, R^(a) is methyl.

In particular embodiments, R^(a) is (C₁-C₄)alkyl, each Hal is —F, n=3,R² is (C₁-C₄)alkyl, R¹ is (C₁-C₄)alkyl, the reaction is heated to about20 to about 120° C., the first acid is p-Toluenesulfonic acid, thesecond acid is acetic acid, and the solvent is acetonitrile.

In particular embodiments, R^(a) is methyl, Hal is —F, n=3, R² is —CH₃,R¹ is —CH₃, the reaction is heated to about 75° C., the first acid isp-Toluenesulfonic acid, the second acid is acetic acid, and the solventis acetonitrile.

O. Cyclization of FF-1 and N-1 to Form G-1

The starting material FF-1, N-1, or a salt or co-crystal thereof, and anadditive are combined with a solvent under conditions effective toproduce G-1.

In certain embodiments, the additive is a carboxylate salt such as, butnot limited to sodium acetate, potassium acetate, lithium acetate,sodium propionate, and potassium propionate. In certain embodiments, theadditive is a carbonate such as, but not limited to sodium carbonate,potassium carbonate, lithium carbonate, and cesium carbonate. In certainembodiments, the additive is a water scavenger such as but not limitedto molecular sieves, trimethyl orthoacetate, and trimethyl orthoformate.In particular embodiments, the additive is potassium acetate.

In certain embodiments, about 1 to about 2 or about 1 to about 1.5equivalents of N-1 or a salt or co-crystal thereof, is used.

In certain embodiments, about 1 to about 5 equivalents of additive areused. In particular embodiments, about 2.5 equivalents of additive isadded.

In certain embodiments, the solvent is acetonitrile, ethyl acetate,toluene, 2-methyl tetrahydrofuran, isopropyl acetate, dichloromethane,or a mixture thereof. In particular embodiments, the solvent isdichloromethane.

In certain embodiments, the reaction is stirred at about 0 to about 40°C., about 10 to about 30° C., about 15 to about 25° C., about 20° C.

In certain embodiments, G-1 is extracted and optionally purified by anysuitable technique known in the art, such as, but not limited to solventextraction, chromatography, crystallization or a combination thereof.

In particular embodiments, the reaction mixture is washed with anaqueous solution and evaporated to dryness. In particular embodiments,the residue is dissolved in dimethylformamide and the resulting solutionis added to water over about 2 hours, while agitating. The productslurry is aged at about 20° C. for about 12 hours and filtered. Theproduct cake is washed with water and dried to afford G-1.

In certain embodiments, N-1 is in solution when added to the reactionmixture.

In further embodiments, L is —CH₂—CH₂—.

In particular embodiments, N-1 is (1R,3S)-3-aminocyclopentan-1-ol:

In particular embodiments, N-1 is a free base or is synthesized and usedwithout isolation.

In particular embodiments, N-1 is a salt or co-crystal. Suitable saltsor co-crystals of N-1 include, but are not limited to, benzoic acid,acetic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid,oxalic acid, hydrochloric acid, naproxen, S-naproxen, R-naproxen,mandelic acid, R-mandelic acid, and S-mandelic acid.

In still further embodiments, N-1 is

In particular embodiments, N-1 is a salt or co-crystal with benzoicacid.

In particular embodiments, N-1 is

In particular embodiments, each Hal is independently —F or —Cl. In aparticular embodiment, each Hal is —F In certain embodiments, n=1-3. Incertain embodiments, n=2. In certain embodiments, n=3.

In certain embodiments, R² is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl (C₁-C₄)alkyl. In certain embodiments, R² is C₁-C₄alkyl. Incertain embodiments, R² is —CH₃.

In certain embodiments, R^(a) is (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁C₄)alkyl. In certain embodiments, R^(a) is (C₁-C₄)alkyl.In certain embodiments, R^(a) is methyl.

In particular embodiments, R^(a) is (C₁-C₄)alkyl, each Hal is —F, n=3,R² is —CH₃, N-1 is

the solvent is dichloromethane, the reaction is stirred at about 0 toabout 40° C. and the additive is potassium acetate.

In particular embodiments, R^(a) is methyl, Hal is —F, n=3, R² is —CH₃,N-1 is

the solvent is dichloromethane, the reaction is stirred at about 20° C.and the additive is potassium acetate.

P. Conversion of (−)-Vince Lactam to b-1 Through a-1

A catalyst, a solvent and (−)-Vince lactam are stirred in a reactor,which is purged with an inert gas. A source of hydrogen is added.

In certain embodiments, the hydrogen source is formic acid, hydrazine,dihydronapthalene, dihydroanthracene, hydrogen gas, or Hantzch ester andisopropanol. In particular embodiments, the hydrogen source is hydrogengas.

In certain embodiments, the catalyst is a platinum catalyst such asPtO₂, a nickel catalyst such as Raney Nickel, a rhodium catalyst such asRhCl(PPh₃)₃, a palladium catalyst, a ruthenium catalyst such as Nyori'scatalyst or an iridium catalyst such as Crabtree's catalyst. In someembodiments, the catalyst is selected form the group consisting of Pd/C,PtO₂, Raney Nickel, RhCl(PPh₃)₃, Nyori's catalyst, and Crabtree'scatalyst. In particular embodiments, the catalyst is Pd/C.

In certain embodiments, the solvent is a polar aprotic solvent such asTHF, 2-MeTHF, dioxane, diethyl ether, diisopropyl ether, DME, MTBE,CPME, EtOAc, and DCM. In certain embodiments, the solvent is a polarprotic solvent such as methanol, ethanol, n-butanol, and isopropanol. Inparticular embodiments, the solvent is 2-methyltetrahydrofuran.

In certain embodiments, the reaction is stirred at about 0 to 65° C.,about 10 to 55° C., about 15 to 45° C., about 20 to 40° C., about 25 to35° C.

In certain embodiments, the reactor is maintained at about 0.30 to about0.35 MPa.

In certain embodiments, the reaction takes place over about 1 to about24 hours, about 1 to about 12 hours, about 3 to about 9 hours, about 6.5hours.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, the reaction is filtered through celite washedwith 2-MeTHF to yield the hydrogenated product in solution.

In certain embodiments, to a solution of the hydrogenated product, asecond catalyst is added, as well as an activated source for aprotecting group.

In certain embodiments, the second catalyst is a nucleophilicamine-containing compound such as imidazole, derivatives of4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine, or a nucleophilicphosphine containing compound such as triphenylphosphine. In particularembodiments, the second catalyst is 4-dimethylaminopyridine (DMAP).

In certain embodiments, the activated source of protecting group isBoc₂O. In particular embodiments, Boc₂O is prepared in solution in2-MeTHF.

In certain embodiments, the protecting group is Boc.

In certain embodiments, the reaction occurs in a polar aprotic solventsuch as THF, EtOAc, DCM, acetonitrile or 2-MeTHF. In particularembodiments, the reaction occurs in 2-MeTHF.

In certain embodiments, the reaction occurs at temperatures in the rangefrom about 20 to 80° C., about 25 to 70° C., about 35 to 60° C., about45 to 50° C.

In certain embodiments, the reaction occurs for about 0.5 to about 12hours, about 1 to about 6 hours, about 1 to about 3 hours, about 2hours.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, the solution is concentrated and a secondsolvent is added.

In certain embodiments, the second solvent is a polar aprotic solventsuch as THF, Dioxane, DME, diisopropyl ether, diethyl ether, MTBE, CPME,2-MeTHF and toluene. In particular embodiments, the second solvent is2-MeTHF.

In certain embodiments, the solution is maintained at about −50 to 30°C., about −50 to 30° C., about −30 to 20° C., about −20 to 10° C., about−10 to 0° C.

Following hydrogenation and addition of the protecting group PG, anucleophile R³M is added to the reaction mixture.

In certain embodiments, nucleophile R³M is a n-alkyl Grignard reagentsuch as ethylmagnesium halides, n-propylmagnesium halides, andn-butylmagnesium halides or an organolithium reagent such as methyllithium, n-butyllithium, and n-hexyllithium. In particular embodiments,the nucleophile is methyl magnesium bromide.

In certain embodiments, nucleophile R³M is added, while maintaining thereaction within the desired temperature range, over about 1 to about 12hours, about 3 to about 9 hours, about 5 to about 7 hours, about 6hours. After the addition is complete, the mixture is stirred for anadditional about 0.5 to about 12 hours, about 0.5 to about 6 hours,about 0.5 to about 4 hours, about 1 to about 2 hours.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, following addition of nucleophile R³M, 15%aqueous AcOH is added while maintaining the temperature at about 0 to 5°C. to adjust the pH to approximately 7. The layers are separated and theorganic layer is washed with water twice. The organic layer isconcentrated to 4 to 5 Volumes under reduced pressure at about ≤45° C.The solution is azeotroped with 2-MeTHF. The final solution isconcentrated under reduced pressure to about 2.5 to 3 Volumes andn-Heptane is slowly added while maintaining the temperature at 30 to 35°C. In certain embodiments, b-1 seeds are added and the mixture isstirred at about 30 to 35° C. for about 5 to 10 hours.

In certain embodiments, additional n-heptane is added while maintainingthe temperature at 30 to 35° C. over approximately 5 h. The contents arecooled to −5 to 0° C. and held for approximately 1 to 2 hours. Theproduct is collected by filtration, washed with n-heptane at −5 to 0°C., and dried under reduced pressure at 40 to 45° C. to afford b-1.

In particular embodiments, the hydrogen source is hydrogen gas, thecatalyst is a palladium catalyst, the solvent for the hydrogenation is2-methyltetrahydrofuran, the hydrogenation reaction is stirred at about0 to about 65° C., the second catalyst is a nucleophilicamine-containing compound, the activated source of protecting group isBoc₂O, the protection reaction occurs in 2-MeTHF at about 25 to 70° C.,the second solvent is 2-MeTHF, and the nucleophile is methyl magnesiumbromide.

In particular embodiments, the hydrogen source is hydrogen gas, thecatalyst is Pd/C, the solvent for the hydrogenation is2-methyltetrahydrofuran, the hydrogenation reaction is stirred at about25 to 35° C., the second catalyst is 4-Dimethylaminopyridine, theactivated source of protecting group is Boc₂O, the protection reactionoccurs in 2-MeTHF at about 45 to 50° C., the second solvent is 2-MeTHF,and the nucleophile is methyl magnesium bromide.

Q. Conversion of b-1 to c-1

To a solution of b-1 in a solvent, an oxidant is added and the reactionis stirred.

In certain embodiments, PG is a protecting group. In certainembodiments, the protecting group PG is Boc.

In certain embodiments, the solvent is a polar aprotic solvent such asDCM, 1,2-dichloroethane, toluene, chlorobenzene, dichlorobenzene,chloroform, carbon tetrachloride and DMF, or a polar protic solvent suchas water, acetic acid, methanol, and ethanol. In particular embodiments,the solvent is toluene.

In certain embodiments, the oxidant is hydrogen peroxide, oxone, t-butylhydrogen peroxide, trifluoroperacetic acid (TFPAA), nitroperbenzoicacid, monopermaleic acid (MPMA), monoperphthalic acid, monoperphthalicacid magnesium salt, persulfuric acid, performic acid, peracetic acid,perbenzoic acid, a silylated peracid, benzeneperoxyseleninic acid,sodium perborate, meta-chloroperoxybenzoic acid, or a resin-boundperacid. In particular embodiments, the oxidant ismeta-chloroperoxybenzoic acid (mCPBA).

In certain embodiments, mCPBA is added in several portions every 4 to 6h.

In certain embodiments, the reaction is stirred within the temperaturerange of −10 to 50° C., 0 to 40° C., 10 to 45° C., 15 to 40° C., 20 to35° C., 25 to 30° C.

In certain embodiments, the reaction is stirred for 1 to 48 h, 6 to 36h, 10 to 20 h.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In particular embodiments, 20% NaHSO₃ is added, then 10% NaOH is added.The organic layer is washed with water and concentrated to afford theoxidized product in solution.

To a solution of the oxidized product, is added water, a solvent and abase or an acid.

In certain embodiments, the solvent is a polar protic solvent such asmethanol, ethanol, isopropanol or water, or a combination of at leastone polar aprotic solvent with a polar aprotic solvent such as THF,Dioxane, DME, disopropylether, diethyl ether, MTBE, CPME, or toluene. Inparticular embodiments, the solvent is a combination of toluene,methanol, and water.

In certain embodiments, the base is an hydroxide base such as lithiumhydroxide, sodium hydroxide and potassium hydroxide or a silanolate basesuch as sodium trimethylsilanolate and potassium trimethylsilanolate. Inparticular embodiments, the base is lithium hydroxide.

In certain embodiments, the acid is a concentrated strong acid such assulfuric and hydrochloric acid.

In certain embodiments, the reaction is stirred at about 0 to 80° C.,about 5 to 70° C., about 10 to 60° C., about 15 to 50° C., about 20 to40° C., about 25 to 30° C.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In particular embodiments, toluene and 25% NaCl are added and the layersseparated. The organic layer is washed with a solution of 20% NaCladjusted to about pH 7 to about pH 8 with 1 N HCl. The organic layer isfiltered and concentrated. Toluene is added and the distillationcontinued. Toluene and active carbon are added. The mixture is warmed toabout 30 to about 40° C. and stirred for about 2 to 6 h. The contentsare cooled, filtered through celite and washed with toluene. Thefiltrate is concentrated. n-heptane is added over about 1 to 2 hours andthe mixture is optionally seeded with c-1 and stirred for an additionalapproximately 2 to 3 hours. n-heptane is added and the mixture isstirred for about 2 to 3 h. The mixture is cooled to about 10 to 15° C.and stirred for an additional approximately 3 to 5 h. The product iscollected by filtration and washed with n-heptane at about 10 to 15° C.The product is dried to afford c-1.

In particular embodiments, the protecting group PG is Boc, the solventis a polar aprotic solvent, the oxidant is mCPBA, the reaction isstirred at 10 to 45° C., the hydrolysis occurs in a combination oftoluene, methanol, and water at about 10 to 60° C., and the base is anhydroxide base.

In particular embodiments, the protecting group PG is Boc, the solventis toluene, the oxidant is mCPBA, the reaction is stirred at 25 to 30°C., the hydrolysis occurs in a combination of toluene, methanol, andwater at about 25 to 30° C., and the base is lithium hydroxide.

R. Resolution of c-1a—Selective Acylation

In certain embodiments, enantioenriched cc-1a is obtained throughenzymatically catalyzed selective acylation.

In this process, the racemic starting material c-1a is a mixture ofcc-1b and cc-1a (i.e., c-1a (+/−) and is dissolved in a solvent.

In certain embodiments, the solvent is a polar aprotic solvent, anon-polar solvent, a polar protic solvent, a mixture of organic solventswith aqueous buffers or a mixture thereof. Exemplary polar aproticsolvents include but are not limited to diethyl ether, diisopropylether, methyl t-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran,dichloromethane and chloroform. Exemplary non-polar solvents include butare not limited to toluene, hexane and heptane. Exemplary polar proticsolvents include but are not limited to t-butanol. In particularembodiments, the solvent used is toluene.

Once the racemic starting material c-1a is dissolved in the solvent,about 1 equivalent of an acyl donor is added. In certain embodiments,the acyl donor is an anhydride or an ester. In certain embodiments, theanhydride include but is not limited to glutaric anhydride and aceticanhydride. In certain embodiments, the ester include but is not limitedto vinyl acetate, isopropenyl acetate, 4-chlorophenyl acetate and ethylmethoxy acetate. In particular embodiments, the acyl donor is glutaricanhydride.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, CN, —NR^(z1)R^(z2), C(O)R^(z1),—C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —OC(O)NR^(z1)R^(z2),—NR^(z1)C(O)R^(z2), —NR^(z1)C(O)NR^(z2), —NR^(z1)C(O)OR^(z2),—S(O)₁₋₂R^(z1), —S(O)₂NR^(z1)R^(z2), —NR^(z1)S(O)₂R^(z2),NR^(z1)S(O)₂R^(z2), and OR^(z1).

In certain embodiments, R^(z1) and R^(z2) are independently selectedfrom the group consisting of H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, 3 to 12 membered heterocyclyl, C₆₋₁₀aryl and 5 to 10 membered heteroaryl.

In certain embodiments, R^(x) is (C₁-C₄)alkyl-R^(y) and R^(y) isselected from the group consisting of H and CO₂H.

In certain embodiments, R^(x) is methyl or (CH₂)₃—CO₂H. In certainembodiments, R^(x) is (CH₂)₃—CO₂H.

About 15% by weight of an enzyme is added. In certain embodiments, theenzyme is a lipase. In certain embodiments, the lipase includes but isnot limited to Novozyme 435, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML.In certain embodiments, the lipase includes but is not limited to CAL-A,CAL-B, PPL, PSL-C, PSL, CRL and MML. In particular embodiments, theenzyme used is Novozyme 435.

In certain embodiments, the reaction is allowed to stir for about 1 to48 h for about 6 to 48 h, for about 12 to 30 h, for about 20 to 26 h,for about 23 h.

In certain embodiments, the reaction is allowed to stir at about 0 to60° C. at about 5 to 30° C., at about 10 to 15° C.

In certain embodiments, additional enzyme is added and the reaction isallowed to proceed for about 1 to 48 h at about 0 to 60° C. In certainembodiments, about 5% by weight of additional enzyme is added and thereaction is allowed to proceed for about 6 to 24 h at about 5 to 30° C.In particular embodiments, additional enzyme is added and the reactionis allowed to proceed for about 12 h at about 10 to 15° C.

In certain embodiments, the ester formed e-1 is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, precipitated enzyme solids are removed byfiltration and rinsed with solvent. The desired e-1 is extracted into abasic aqueous layer such as aqueous Na₂CO₃. The aqueous is washed withan organic solvent (such as MTBE) to remove undesired material. Asolvent (such as THF) is then added to the aqueous layer, which containse-1, followed by hydroxide.

In certain embodiments, the solvent is a polar aprotic solvent.Exemplary polar aprotic solvent include but are not limited to diethylether, diisopropyl ether, methyl t-butyl ether, 2-methyltetrahydrofuran,tetrahydrofuran, dichloromethane and chloroform. In particularembodiments, the solvent is THF.

Exemplary sources of hydroxide include but are not limited to sodiumhydroxide, potassium hydroxide and lithium hydroxide. In particularembodiments, the source of hydroxide is sodium hydroxide.

In certain embodiments, the mixture is allowed to stir for about 1 to 24h at about 0 to 60° C. In certain embodiments, the mixture is allowed tostir for about 1 to 12 h at about 5 to 30° C. In particular embodiments,the mixture is allowed to stir for about 4 h at about 15 to 20° C.

In certain embodiments, the product cc-1a is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In particular embodiments, the layers are separated, and the organiclayer is concentrated.

In certain embodiments, the organic phase is concentrated and cc-1a isrecrystallized in a solvent with the addition of seeds of cc-1a. Incertain embodiments, the solvent is a mixture of THF, dichloromethaneand water, and the recrystallization is conducted at about 40 to 50° C.

In certain embodiments, the enantiomeric excess (% ee) of the product isabout 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100,about 98 to 100, about 98.5 to 100, about 98.5 to 99, about 99 to 100,about 99.5 to 100, about 99.9 to 100.

In particular embodiments, c-1a is dissolved in a nonpolar solvent, theacyl donor is glutaric anhydride, R^(x) is (CH₂)₃—CO₂H, the enzyme usedis a lipase, the reaction is stirred at about 10 to 15° C., cc-1 b isremoved by filtration, the hydrolysis occurs in THF at about 5 to 30°C., and the source of hydroxide is sodium hydroxide.

In particular embodiments, c-1a is dissolved in toluene, the acyl donoris glutaric anhydride, R^(x) is (CH₂)₃—CO₂H, the enzyme used is Novozyme435, the reaction is stirred at about 10 to 15° C., cc-1b is removed byfiltration, the hydrolysis occurs in THF at about 15 to 20° C., and thesource of hydroxide is sodium hydroxide.

S. Resolution of c-1a—Selective Hydrolysis

In certain embodiments, enantioenriched cc-1a is obtained throughenzymatically catalyzed selective hydrolysis.

A mixture of the starting material, c-1a, an acyl donor, a base and acatalyst in a solvent, is stirred.

In certain embodiments, the acyl donor includes but is not limited to ananhydride or an acid chloride. In certain embodiments, the anhydrideincludes but is not limited to succinic anhydride and acetic anhydride.In certain embodiments, the acid chloride include but is not limited toacetyl chloride and benzoyl chloride. In particular embodiments, theacyl donor is glutaric anhydride.

In certain embodiments, R^(x) is (C₁-C₆)alkyl-R^(y) and R^(y) isselected from the group consisting of H, CN, —NR^(z1)R^(z2)C(O)R^(z1),—C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —OC(O)NR^(z1)R^(z2),—NR^(z1)C(O)R^(z2), —NR^(z1)C(O)NR^(z2), —NR^(z1)C(O)OR^(z2), —SR^(z1),—S(O)₁₋₂R^(z1), —S(O)₂NR^(z1)R⁷⁻², —NR^(z1)S(O)₂R^(z2),NR^(z1)S(O)₂R^(z2), and OR^(z1).

In certain embodiments, R^(z1) and R^(z2) are independently selectedfrom the group consisting of H, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, 3 to 12 membered heterocyclyl,C₆₋₁₀aryl and 5 to 10 membered heteroaryl.

In certain embodiments, R^(x) is (C₁-C₄)alkyl-R^(y) and R^(y) isselected from the group consisting of H and CO₂H.

In certain embodiments, R^(x) is methyl or (CH₂)₃—CO₂H. In certainembodiments, R^(x) is (CH₂)₃—CO₂H.

In certain embodiments, the catalyst includes but is not limited tonucleophilic amine-containing compounds and nucleophilic phosphinecontaining compounds. In certain embodiments, the nucleophilicamine-containing compounds include but are not limited to imidazole,derivatives of 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine. In certainembodiments, the nucleophilic phosphine containing compounds include butare not limited to triphenylphosphine. In particular embodiments, thecatalyst is 4-dimethylaminopyridine.

In certain embodiments, the base includes but is not limited to aminebases, aromatic amine bases, inorganic carbonates, metal hydrides andalkoxides. In certain embodiments, the amine bases include but are notlimited to N,N-diisopropylethylamine, quinuclidine,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,tripropylamine, and tributylamine. In certain embodiments, the aromaticamine bases include but are not limited to pyridine. In certainembodiments, the inorganic carbonate bases include but are not limitedto lithium carbonate, sodium carbonate, potassium carbonate, and cesiumcarbonate. In certain embodiments, the metal hydride bases include butare not limited to sodium hydride, and potassium hydride. In certainembodiments, the alkoxide bases include but are not limited to sodiummethoxide, sodium tert-butoxide and lithium tert-butoxide. In particularembodiments, the base is pyridine.

In certain embodiments, the solvent is an aromatic solvent or a polarnon-protic solvent. In certain embodiments, the aromatic solventincludes but is not limited to pyridine, toluene, xylene, benzene, andchlorobenzene. In certain embodiments, the polar non-protic solventincludes but is not limited to N,N-dimethylformamide,N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, anddichloromethane. In particular embodiments, the solvent is Pyridine.

In certain embodiments, the reaction mixture is stirred for about 1 to48 h, for about 6 to 24 h, for about 12 h.

In certain embodiments, the reaction mixture is stirred at about 0 to120° C., at about 20 to 100° C., at about 40 to 80° C., or at about 60°C.

In certain embodiments, the product ee-1 is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In particular embodiments, the reaction mixture is evaporated todryness, dissolved in DCM and washed with a 0.2 M HCl aqueous solution.The organic layer is evaporated to dryness. The residue is stirred withwater and the pH adjusted to about 7.8 with a 2 M NaOH solution. Thewater layer is washed with DCM. The water layer is then acidified to pH4 with 3 N HCl aqueous solution and extracted DCM. The combined organiclayers are dried over Na₂SO₄, filtered and evaporated. Trituration withpentane followed by filtration and drying under vacuum yields ee-1.

ee-1 is suspended in a solvent, an enzyme is added.

In certain embodiments, the solvent is a polar aprotic solvent, anon-polar solvent or a mixtures of organic solvents with aqueousbuffers. In certain embodiments, the polar aprotic solvent includes butis not limited to diethyl ether, diisopropyl ether, methyl t-butylether, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane, andchloroform. In certain embodiments, non-polar solvents include but arenot limited to hexane and heptane. In particular embodiments, thesolvent is diisopropyl ether:phosphate buffer 1:2.

In certain embodiments, the enzyme is a lipase such as but are notlimited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In particularembodiments, the enzyme is CAL-B.

In certain embodiments, the reaction is stirred at 0 to 60° C., at 10 to50° C., at 20 to 40° C., at about 30° C.

In certain embodiments, the reaction is stirred for 24 to 200 h, 50 to150 h, about 100 h.

In certain embodiments, the product cc-1a is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, e-2 is removed by extraction with an aqueouslayer. In certain embodiments, the product e-2 is removed by extractionin a basic aqueous layer.

In particular embodiments, the reaction mixture is filtered and thelayers of the filtrate are separated. The solid is washed with DCM andthe filtrate is used to extract the aqueous layer. The combined organiclayers are washed with 5% Na₂CO₃, brine and dried. Filtration andevaporation of the volatiles under reduced pressure affords cc-1a.

In particular embodiments, the acyl donor is an anhydride, R^(x) is(C₁-C₄)alkyl-R^(y).R^(y) is selected from the group consisting of H andCO₂H, the catalyst is 4-dimethylaminopyridine, the base for the firststep is pyridine, the solvent for the first step is an aromatic solvent,the reaction mixture in the first step is stirred at about 0 to about60° C., the solvent for the hydrolysis is diisopropyl ether:phosphatebuffer 1:2, the enzyme is CAL-B, and hydrolysis reaction is stirred atabout 0 to about 30° C.

In particular embodiments, the acyl donor is glutaric anhydride, R″ is(CH₂)₃—CO₂H, the catalyst is 4-dimethylaminopyridine, the base for thefirst step is pyridine, the solvent for the first step is pyridine, thereaction mixture in the first step is stirred at about 60° C., thesolvent for the hydrolysis is diisopropyl ether:phosphate buffer 1:2,the enzyme is CAL-B, the hydrolysis reaction is stirred at about 30° C.,and e-2 is removed by extraction in a basic aqueous layer.

In certain embodiments, the enantiomeric excess (% ee) of the product isabout 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100,about 98 to 100, about 98.5 to 100, about 98.5 to 99, about 99 to 100,about 99.5 to 100, about 99.9 to 100.

T. Classical Resolution of c-1a

In certain embodiments, c-1a is resolved via a classical resolutionprocess. In this process, c-1a, an acid, and a solvent are combined.

In certain embodiments, the acid is selected from the group consistingof:

-   -   single enantiomers of carboxylic acids including but not limited        to: naproxen, phenyl succinic acid, malic acid,        2-phenylpropionic acid, alpha-methoxyphenyl acetic acid,        tartranilic acid, 3-phenyllactic acid, α-hydroxyisovaleric acid,        2′-methoxy-tartranilic acid, (alpha-methylbenzyl)phthalamic        acid, 2′-chloro-tartranilic acid, pyroglutamic acid;    -   single enantiomers of mandelic acid derivatives including but        not limited to: mandelic acid, 2-chloromandelic acid,        4-bromo-mandelic acid, 0-acetyl mandelic acid, 4-methyl-mandelic        acid;    -   single enantiomers of sulfonic acids including but not limited        to: camphor sulfonic acid;    -   single enantiomers of tartaric acid derivatives including but        not limited to: tartaric acid, dibenzoyl tartaric acid hydrate,        di-p-anisoyltartaric acid, di-toluyltartaric acid, dibenzoyl        tartaric acid hydrate;    -   single enantiomers of phosphoric acid derivatives including but        not limited to: phencyphos hydrate, chlocyphos, anisyphos, BINAP        phosphate; and    -   single enantiomers of amino acids including but not limited to:        N-acetyl-phenylalanine, N-acetyl-leucine, N-acetyl-proline,        boc-phenylalanine, and boc-homophenylalanine.

In some embodiments, the acid is (S)-Naproxen or S-(+)-mandelic acid. Inparticular embodiments, the acid is (S)-Naproxen. In particularembodiments, the acid is S-(+)-mandelic acid.

In certain embodiments, the solvent is water, acetonitrile, ethanol,isopropanol, methyl ethyl ketone, isopropyl acetate, dioxane, a mixtureof water and a water-miscible organic solvents such as ethanol andisopropanol, an halogenated solvent such as dichloromethane andchloroform. In particular embodiments, the solvent is water orisopropanol or a mixture thereof. In particular embodiments, the solventis water. In particular embodiments, the solvent is isopropanol.

In certain embodiments, the reaction is stirred at 0 to 120° C., 2 to120° C., 50 to 120° C., 80 to 120° C., about 100° C. In certainembodiments, the reaction is stirred at about 20° C.

In certain embodiments, the product is extracted and optionally purifiedby any suitable technique known in the art, such as, but not limited tosolvent extraction, chromatography, crystallization or a combinationthereof.

In certain embodiments, dd-1 precipitates out of solution and isfiltered. The solid may be further recrystallized in a solvent such asisopropanol.

In particular embodiments, removal of the solvent by evaporation yieldsa mixture of dd-1 and dd-2. The mixture is suspended in a solvent.

In certain embodiments, dd-1 is selectively recrystallized.

In certain embodiments, the solvent is water, acetonitrile, ethanol,isopropanol, methyl ethyl ketone, isopropyl acetate, dioxane; a mixtureof water and water-miscible organic solvents such as ethanol andisopropanol, or a halogenated solvent such as dichloromethane orchloroform. In particular embodiments, the solvent is a mixture ofmethyl ethyl ketone and water.

In certain embodiments, the mixture is stirred at about 0 to 100° C.,about 20 to 80° C., about 40 to 60° C.

In certain embodiments, the mixture is allowed to cool to roomtemperature and the solid is isolated by filtration, dried andrecrystallized from 10% water in methyl ethyl ketone to provideenantioenriched dd-1.

In particular embodiments, the acid is S-(+)-mandelic acid or(S)-Naproxen, the solvent is water or isopropanol, the reaction isstirred at about 0 to about 20° C., and dd-1 the product is isolated bysolvent extraction, chromatography, crystallization or a combinationthereof.

In particular embodiments, the acid is S-(+)-mandelic acid, the solventis isopropanol, the reaction is stirred at about 20° C., and dd-1precipitates out of solution.

In particular embodiments, the acid is the acid is (S)-Naproxen, thesolvent is water, the reaction is stirred at about 20° C., and dd-1 isselectively recrystallized in a mixture of methyl ethyl ketone andwater.

In certain embodiments, the enantiomeric excess (% ee) of the product isabout 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100,about 98 to 100, about 98.5 to 100, about 98.5 to 99, about 99 to 100,about 99.5 to 100, about 99.9 to 100.

U. Allylic Amination

In certain embodiments, an allylic amination process for obtaining g-1xis provided. In this process, a ligand and a catalyst are mixed indegassed solvent, followed by addition of f-1x, a base and anucleophile.

In certain embodiments, the ligand is absent, tricyclohexylphosphine,1,3-bis(diphenylphosphino)propane; 1,2-bis(diphenylphosphino)ethane,triphenylphosphine or 1,1′-bis(diphenylphosphino)ferrocene. Inparticular embodiments, the ligand is triphenylphosphine.

In certain embodiments, the catalyst is a Palladium catalyst such asPd(OAc)₂, PdCl₂(PPh₃), Pd(tBu₂Ph)₂Cl₂,Tris(dibenzylideneacetone)dipalladium(0) and Pd(amphos)₂Cl₂. Inparticular embodiments, the catalyst isTris(dibenzylideneacetone)dipalladium(0).

In certain embodiments, the solvent is an ether such as dimethoxyethane,THF or MeTHF, an aromatic solvent such as toluene and benzene. Inparticular embodiments, the solvent is THF.

In certain embodiments, the base is potassium isopropoxide, cesiumhydroxide, Hunig's base or a carbonate base such as cesium carbonate,potassium carbonate and sodium carbonate. In particular embodiments, thebase is cesium carbonate.

In certain embodiments, the nucleophile is a phthalamide such aspotassium phthalamide, an azide such as sodium azide or TMS-azide, anamine such as benzylamine or dibenzylamine, a carboxylate such asdi-tert-butyl iminodicarboxylate. In particular embodiments, thenucleophile is di-tert-butyl iminodicarboxylate.

In certain embodiments, about 1 equivalent of nucleophile is added.

In certain embodiments, the reaction is stirred at about 20 to 80° C.,about 30 to 70° C., about 40 to 60° C., about 50° C.

In certain embodiments, the mixture is heated to about 50° C. forapproximately 18 h.

In certain embodiments, the product formed is extracted and optionallypurified by any suitable technique known in the art, such as, but notlimited to solvent extraction, chromatography, crystallization or acombination thereof.

In certain embodiments, the mixture is cooled and water and ethylacetate are added. The layers are separated and the organic phase iswashed with ethyl acetate. The combined organics are concentrated todryness. The residue is purified by silica gel column chromatography (0to 40% ethyl acetate in hexane). The isolated material is dissolved inMeTHF, washed with 5% aq. KOH, concentrated, and purified by silica gelcolumn chromatography (0 to 10% methanol in dichloromethane) to provideg-1x.

In particular embodiments, the ligand is triphenylphosphine, thecatalyst is a palladium cataloyst, the solvent is an ether, the base isa carbonate base, the nucleophile is di-tert-butyl iminodicarboxylate,and the reaction is stirred at about 20 to about 80° C.

In particular embodiments, the ligand is triphenylphosphine, thecatalyst is Tris(dibenzylideneacetone)dipalladium(0), the solvent isTHF, the base is cesium carbonate, the nucleophile is di-tert-butyliminodicarboxylate, and the reaction is stirred at about 50° C.

V. Hydrogenation

In certain embodiments, a hydrogenation process for obtaining h-1x isprovided. In this process, g-1x and a catalyst are combined in asolvent, followed by addition of a source of hydrogen.

In certain embodiments, the catalyst is a platinum catalyst such asPtO₂, a palladium catalyst, a nickel catalyst such as Raney Nickel, arhodium catalyst such as RhCl(PPh₃)₃, a ruthenium catalyst such asNyori's catalyst, or an iridium catalyst such as Crabtree's catalyst. Insome embodiments, the catalyst is selected form the group consisting ofPd/C, PtO₂, Raney Nickel, RhCl(PPh₃)₃, Nyori's catalyst, and Crabtree'scatalyst. In particular embodiments, the catalyst is PtO₂.

In certain embodiments, the solvent is a polar aprotic solvent such asTHF, 2-MeTHF, dioxane, diethyl ether, diisopropyl ether, DME, MTBE,CPME, EtOAc and DCM or a polar protic solvent such as methanol,isopropanol, ethanol, and n-butanol. In particular embodiments, thesolvent is isopropanol.

In certain embodiments, the reaction is stirred at about 0 to 65° C.,about 5 to 55° C., about 10 to 45° C., about 10 to 35° C., or about 15to 25° C.

In certain embodiments, the source of hydrogen is formic acid,hydrazine, dihydronapthalene, dihydroanthracene, H₂ gas or Hantzch esterand isopropanol. In particular embodiments, the source of hydrogen is H₂gas. In particular embodiments, the source of hydrogen is an atmosphereof hydrogen.

In certain embodiments, the reaction is stirred for 1 to 48 h, 6 to 24h, 10 to 20 h, 16 to 20 h, or about 18 h.

In certain embodiments, h-1x is extracted and optionally purified by anysuitable technique known in the art, such as, but not limited to solventextraction, chromatography, crystallization or a combination thereof.

In certain embodiments, the mixture is filtered through celite and usedwithout further purification in the subsequent deprotection.

In particular embodiments, the catalyst is a platinum catalyst, thesolvent is a polar protic solvent, the reaction is stirred at about 5 to55° C., and the source of hydrogen is H₂ gas.

In particular embodiments, the catalyst is PtO₂, the solvent isisopropanol, the reaction is stirred at about 15 to 25° C., and thesource of hydrogen is H₂ gas.

W. Deprotection

In certain embodiments, a deprotection process for obtaining N-1x isprovided. In this process, h-1x is added to an acid in a solvent.

In certain embodiments, the acid is a sulfonic acid such asmethanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid,an inorganic acid such as phosphoric acid, hydrochloric acid andsulfuric acid, a carboxylic acid such as trifluoroacetic acid, oxalicacid and benzoic acid. In particular embodiments, the acid is anhydroushydrochloric acid.

In certain embodiments, the solvent is an alcoholic solvent such asmethanol, isopropanol and ethanol, or a polar aprotic solvent such asdioxane, acetonitrile and dichloromethane, or water. In certainembodiments, the solvent is an alcoholic solvent. In certainembodiments, the solvent is a polar aprotic solvent. In certainembodiments, the solvent is water. In certain embodiments, the solventis methanol, isopropanol, ethanol, dioxane, acetonitrile,dichloromethane, or water. In particular embodiments, the solvent isisopropanol.

In certain embodiments, the reaction is stirred at about 0 to 80° C.,about 0 to 60° C., about 5 to 45° C., about 10 to 35° C., or about 15 to25° C.

In certain embodiments, about 1 to 10 equivalents, about 5 to 10equivalents, or about 7 equivalents of acid is used.

In certain embodiments, the reaction is stirred for about 1 to 48 h,about 6 to 24 h, about 12 to 24 h, or about 18 h.

In certain embodiments, the product formed, N-1x, is extracted andoptionally purified by any suitable technique known in the art, such as,but not limited to solvent extraction, chromatography, crystallizationor a combination thereof.

In particular embodiments, the reaction is cooled to approximately 0° C.and the product N-1x is collected by filtration.

In particular embodiments, the acid is an inorganic acid, the solvent isan alcoholic solvent, and the reaction is stirred at 5 to 45° C.

In particular embodiments, the acid is anhydrous hydrochloric acid, thesolvent is isopropanol, and the reaction is stirred at 15 to 25° C.

EXAMPLES

In order for this invention to be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating embodiments, and are not to be construed as limiting thescope of this disclosure in any way. The reactants used in the examplesbelow may be obtained either as described herein, or if not describedherein, are themselves either commercially available or may be preparedfrom commercially available materials by methods known in the art.

In one embodiment, a multi-step synthetic method for preparing acompound of Formula I is provided, as set forth below. In certainembodiments, each of the individual steps of the Schemes set forth belowis provided. Examples and any combination of two or more successivesteps of the below Examples are provided.

A. Acylation and Amidation of Meldrum's Acid to Form C-1a:

In a reaction vessel, Meldrum's acid (101 g, 1.0 equivalent) and4-dimethylaminopyridine (1.8 g, 0.2 equivalents) were combined withacetonitrile (300 mL). The resulting solution was treated withmethoxyacetic acid (6.2 mL, 1.2 equivalents). Triethylamine (19.4 mL,2.0 equivalents) was added slowly to the resulting solution, followed bypivaloyl chloride (9.4 mL, 1.1 equivalents). The reaction was thenheated to about 45 to about 50° C. and aged until consumption ofMeldrum's acid was deemed complete.

A separate reaction vessel was charged with acetonitrile (50 mL) andJ-1a (13.4 g, 1.2 equivalents). The resulting solution was treated withtrifluoroacetic acid (8.0 mL, 1.5 equivalents), and then this acidicsolution was added to the acylation reaction in progress at about 45 toabout 50° C.

The reaction was allowed to age for at least 18 hours at about 45 toabout 50° C., after which time the solvent was removed under reducedpressure. The crude residue was dissolved in ethyl acetate (150 mL), andthe organic layer was washed with water. The combined aqueous layerswere extracted with ethyl acetate. The combined organic layers werewashed with saturated sodium bicarbonate solution, and the combinedbicarbonate washes were back extracted with ethyl acetate. The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting crude material waspurified twice via silica gel chromatography to yield C-1a.

¹H NMR (400 MHz, CDCl₃): δ 7.12 (br, 1H), 6.66 (app t, J=8.1 Hz, 2H),4.50 (app d, J=5.7 Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H).¹³C NMR (100 MHz, CDCl₃): δ 203.96, 164.90, 162.37 (ddd, J=250.0, 15.7,15.7 Hz), 161.71 (ddd, J=250.3, 14.9, 10.9 Hz), 110.05 (ddd, J=19.7,19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t, J=3.5 Hz).LCMS, Calculated: 275.23, Found: 275.97 (M).

B. Alkylation of C-1a to Form E-1a:

A solution of C-1a (248 mg, 1.0 equivalent) and 2-methyl tetrahydrofuran(1.3 mL) was treated with N,N-dimethylformamide dimethylacetal (0.1 mL,1.1 equivalent) and stirred at room temperature overnight (˜14 hours).The reaction was treated with aminoacetaldehyde dimethyl acetal (0.1 mL,1.0 equivalents), and was allowed to age for about 2 hours, and then wasquenched via the addition of 2 N HCl (1.5 mL).

The reaction was diluted via the addition of ethyl acetate, and phaseswere separated. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified via silica gel chromatography to yield E-1a.

¹H NMR (400 MHz, CDCl₃): δ 10.85 (s, 1H), 9.86 (s, 1H), 8.02 (d, J=13.1Hz, 1H), 6.65 (dd, J=8.7, 7.7 Hz, 2H), 4.53 (d, J=3.9 Hz, 2H), 4.40 (t,J=5.1 Hz, 1H), 4.18 (s, 2H), 3.42 (s, 6H), 3.39 (m, 2H), 3.37 (s, 3H).¹³C NMR (100 MHz, CDCl₃): δ 193.30, 169.15, 162.10 (ddd, J=248.9, 15.5,15.5 Hz), 161.7 (ddd, J=250.0, 14.9, 11.1 Hz), 161.66, 111.08 (dddJ=19.9, 19.9, 4.7 Hz) 103.12, 100.29 (ddd, 0.1=28.1, 17.7, 2.3 Hz),76.30, 58.83, 54.98, 53.53, 51.57, 29.89 (t, J=3.3 Hz). LCMS,Calculated: 390.36, Found: 390.92 (M).

C. Cyclization of E-1a to Form F-1a:

E-1a (0.2 g, 1.0 equivalent), dimethyl oxalate (0.1 g, 2.5 equivalents)and methanol (1.5 mL) were combined and cooled to about 0 to about 5° C.Sodium methoxide (0.2 mL, 30% solution in methanol, 1.75 equivalents)was introduced to the reaction slowly while keeping the internaltemperature of the reaction below about 10° C. throughout the addition.After the addition was completed the reaction was heated to about 40 toabout 50° C. for at least 18 hours.

After this time had elapsed, the reaction was diluted with 2 N HCl (1.5mL) and ethyl acetate (2 mL). The phases were separated, and the aqueousphase was extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered, and solventwas removed under reduced pressure. The resulting crude oil was purifiedvia silica gel chromatography to afford F-1a.

¹H NMR (400 MHz, CDCl₃): δ 10.28 (t, J=5.5 Hz, 1H), 8.38 (s, 1H),6.66-6.53 (m, 2H), 4.58 (d, J=5.6 Hz, 2H), 4.43 (t, J=4.7 Hz, 1H), 4.00(d, J=4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). ¹³C NMR(100 MHz, CDCl₃): δ 173.08, 163.81, 162.17, 162.14 (ddd, J=249.2, 15.6,15.6 Hz), 161.72 (ddd, J=250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98,119.21, 110.53 (ddd, J=19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68,56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15(M+H).

D. Alkylation and Cyclization of C-1a to Form F-1a:

To a reaction vessel were added C-1a (245 mg, 1.0 equivalent) andN,N-dimethylformamide dimethylacetal (0.5 mL, 4.3 equivalent). Thereaction mixture was agitated for approximately 30 minutes. The reactionwas then treated with 2-methyl tetrahydrofuran (2.0 mL) andaminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalent). The reactionwas allowed to age for several hours and then solvent was removed underreduced pressure.

The resulting material was dissolved in methanol and dimethyl oxalatewas added (0.3 g, 2.5 equivalents). The reaction mixture was cooled toabout 0 to about 5° C., and then sodium methoxide (0.4 mL, 30% solutionin methanol, 1.75 equivalents) was introduced to the reaction slowly.After the addition was completed the reaction was heated to about 40 toabout 50° C.

After this time had elapsed, the reaction was cooled to room temperatureand quenched via the addition of 2 N HCl (1.5 mL). The reaction was thendiluted with ethyl acetate, and the resulting phases were separated. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified via silica gelchromatography to yield F-1a.

¹H NMR (400 MHz, CDCl₃): δ 10.28 (t, J=5.5 Hz, 1H), 8.38 (s, 1H),6.66-6.53 (m, 2H), 4.58 (d, J=5.6 Hz, 2H), 4.43 (t, J=4.7 Hz, 1H), 4.00(d, J=4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). ¹³C NMR(100 MHz, CDCl₃): δ 173.08, 163.81, 162.17, 162.14 (ddd, J=249.2, 15.6,15.6 Hz), 161.72 (ddd, J=250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98,119.21, 110.53 (ddd, J=19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68,56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15(M+H).

E. Condensation of F-1a with N-1a to form G-1a:

To a reaction vessel were added F-1a (202 mg, 1.0 equivalent) andacetonitrile (1.4 mL). The resulting solution was treated with glacialacetic acid (0.2 mL, 6.0 equivalents) and methane sulfonic acid (0.01mL, 0.3 equivalents). The reaction was then heated to about 70 to about75° C.

After 3 hours, a solid mixture of N-1a (0.128 g, 1.5 equivalents) andpotassium carbonate (0.2 g, 2.7 equivalents) was introduced to thereaction at about 70 to about 75° C. After the addition was completed,the reaction was allowed to progress for at least about 1 hour.

After this time had elapsed, water (1.4 mL) and dichloromethane (1.4 mL)were introduced to the reaction. The phases were separated, and theaqueous layer was extracted with dichloromethane. The combined organiclayers were dried over magnesium sulfate, then were filtered andconcentrated under reduced pressure. The resulting crude material waspurified via silica gel chromatography to obtain G-1a.

¹H NMR (400 MHz, CDCl₃): δ 10.23 (t, J=5.5 Hz, 1H), 8.39 (s, 1H), 6.60(t, J=8.1 Hz, 2H), 5.29 (dd, J=9.5, 3.7 Hz, 2H), 4.57 (d, J=5.4 Hz, 3H),4.33 (dd, J=12.8, 3.8 Hz, 1H), 4.02-3.87 (m, 1H), 3.94 (s, 3H),2.06-1.88 (m, 4H), 1.78 (dd, J=17.2, 7.5 Hz, 1H), 1.55-1.46 (m, 1H). ¹³CNMR (100 MHz, CDCl₃): δ 174.53, 163.75, 162.33 (dd, J=249.4, 15.7, 15.7Hz), 161.86 (ddd, J=250.4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44,129.75, 118.88, 110.58 (ddd, J=19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64,74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS,Calculated: 463.14, Found: 464.15 (M+H).

F. Deprotection of G-1a to Form a Compound of Formula Ia:

G-1a (14 g) was suspended in acetonitrile (150 mL) and dichloromethane(150 mL). MgBr₂ (12 g) was added. The reaction was heated to 40 to 50°C. for approximately 10 min before being cooled to room temperature. Thereaction was poured into 0.5M HCl (140 mL) and the layers separated. Theorganic layer was washed with water (70 mL), and the organic layer wasthen concentrated. The crude product was purified by silica gelchromatography (100% dichloromethane up to 6% ethanol/dichloromethane)to afford Ia.

G. Hydrolysis of F-1a to Form II-a:

To a reaction vessel were added F-1a (480 mg, 1.0 equiv.), methanol (5.8mL) and water (2.4 mL). To the resulting homogeneous solution, lithiumhydroxide monohydrate (88 mg, 2.0 equiv.) is added. The resultingsuspension was stirred at room temperature for about 17 hours.

Water (15 mL) and ethyl acetate were added, then 1N HCl was addeddropwise until the pH was about 3. The layers were mixed and separated,the aqueous layer extracted with ethyl acetate (15 mL), and the combinedorganic layers dried over Na₂SO₄. The organic layer was removed byevaporation. The aqueous layer was then brought to pH<2, and extractedtwice with ethyl acetate (2×15 mL). The combined organic layers weredried over Na₂SO₄, mixed with the residue from the previous extractionand the solvent was removed by evaporation. The residue was taken up inMTBE (2.4 mL), to form a slurry, which was filtered and washed with MTBEto provide 1002.

¹H NMR (400 MHz, CDCl₃): δ 10.43 (t, J=5.2 Hz, 1H), 9.65 (bs, 1H), 8.52(s, 1H), 6.67 (t, J=8.0 Hz, 2H), 4.67 (d, J=6.0 Hz, 2H), 4.58 (t, J=4.8Hz, 1H), 4.16 (d, J=4.8 Hz, 1H), 3.91 (s, 3H), 3.37 (s, 6H). ¹³C NMR(100 MHz, CDCl₃): δ 173.04, 164.15, 162.10, 148.63, 145.28, 137.25,118.66, 102.46, 100.35 (t, J=30.7 Hz), 87.42, 61.30, 57.09, 55.55,30.94.

H. Preparation of BB-1a from B-1a:

To a reaction vessel was added B-1a (0.2 g, 1.0 equivalent) and3-pentanone (1.0 mL, 10.0 equivalents). These compounds were thendissolved in toluene (1.0 mL) and heated to about 110 to about 115° C.The reaction was maintained at this temperature for about 4 hours, afterwhich time the reaction was cooled to room temperature and solvent wasremoved. The resulting crude material was purified over silica gel toafford BB-1a.

¹H NMR (400 MHz, CDCl₃): δ 5.46 (t, J=1.1 Hz, 1H), 3.97 (d, J=1.0 Hz,2H), 3.42 (s, 3H), 1.99 (m, 4H), 0.98 (t, J=7.5 Hz, 6H). ¹³C NMR (100MHz, CDCl₃): δ 167.63, 160.94, 111.05, 93.04, 70.07, 59.27, 28.08, 7.40.LCMS, Calculated: 200.10, Found 200.79 (M+).

I. Preparation of C-1a from BB-1a:

To a reaction vessel was added BB-1a (0.08 g, 1.0 equivalent) and N-1a(0.08 g, 1.1 equivalents). These compounds were then dissolved intoluene (1.5 mL) and heated to about 115° C. After about 1 h, thereaction was cooled and solvent was removed. The resulting crudematerial was purified via silica gel chromatography to obtain C-1a.

All spectral data collected for C-1a matched that provided above.

J. Formation of B-1a.J-1a Salt:

The free acid of B-1a (4.4 g) was dissolved in 50 mL acetonitrile andJ-1a (3.3 g, 1.0 equivalent) in 30 mL acetonitrile was added. Thedesired salt was obtained and was aged for about one hour at roomtemperature. The solids were filtered and the cake was rinsed with 2×10mL acetonitrile to afford the product.

NMR (400 MHz, DMSO-d⁶) δ 7.40 (bs, 3H), 6.11 (t, J=7.7 Hz, 2H), 3.12 (s,2H), 2.92 (s, 2H), 2.08 (s, 3H), 0.35 (s, 6H). ¹³C NMR (101 MHz,DMSO-d⁶) δ 191.98, 164.66, 163.06 (dt, J=248.6, 16.2 Hz), 161.82 (ddd,J=250.4, 15.8, 10.4 Hz), 107.39 (td, J=20.0, 4.7 Hz), 101.16 (m),100.01, 87.01, 77.71, 58.39, 30.45, 26.37.

K. Formation of B-1a.J-1a Salt:

Meldrum's acid (10.1 g, 1.1 equivalents) and DMAP (0.6 g, 0.08equivalents) were dissolved in 300 mL acetonitrile. Methoxyacetic acid(5.8 g, 1 equivalents) and 17.6 g (2.1 equivalents) Hunig's base wereadded. The solution was warmed to about 45° C. and 8.4 g (1.1equivalents) of pivaloyl chloride in 30 mL of acetonitrile was addedover about 1 hour.

After about 2.5 hours at about 45° C., the solution was cooled to roomtemperature and was concentrated under vacuum. The resulting oil wasdissolved in 110 mL dichloromethane, cooled over ice bath, and extractedwith 50 mL 1N HCl. The layers were separated, and the aqueous layer wasextracted with 40 mL dichloromethane. The combined organic layer wasconcentrated and diluted in acetonitrile and evaporated again. Thematerial was dissolved in 220 mL acetonitrile.

After cooling over an ice bath, trifluorobenzylamine (11.4 g, 1.1equivalents) and the mixture at about 9° C. was allowed to warm up toroom temperature and agitated as the slurry thickened. After about 2hours, 220 mL MTBE was added slowly and the slurry was aged overnight.The slurry was cooled over ice bath for about 3 hours and was filtered,rinsed with 50 mL cold 1:1 acetonitrile/MTBE, and dried overnight in avacuum oven to afford the product.

L. Amidation Using the B-1a.J-1a Salt to Form C-1a

The salt B-1a.J-1a (3.7 g, 1.0 equivalent) was suspended in 50 mL ofacetonitrile, and then was treated with trifluoroacetic acid (0.1 mL,0.1 equivalent). The reaction was heated to about 40 to about 50° C. forapproximately 18 hours, and then cooled to room temperature. Solvent wasremoved under reduced pressure, and the resulting residue was suspendedin 5 volumes of 2-methyl tetrahydrofuran and 5 volumes of hexanes wereadded dropwise over 1 h. The resulting mixture was allowed to stir forat least 24 hours, and then the resulting slurry was filtered to affordthe product.

M. Amidation of B-1a.J-1a to C-1a:

B-1a.J-1a (75.077 g, 198.97 mmol, 1.0 equivalent), acetonitrile (750mL), and trifluoroacetic acid (1.5 mL, 20 mmol, 0.1 equiv) were combinedin a reactor. The reactor was heated until the internal temperaturereached about 58° C., and the reactor contents were aged between about58-61° C. for about 3.5 hours. The jacket temperature was then adjustedto about 45° C. and vacuum was applied. The reactor contents weredistilled until about 150 mL remained. iso-Propylacetate (300 mL) wasthen charged to the reactor, and distillation was continued until thevolume reached about 150 mL. iso-Propylacetate (150 mL) was then chargedto the reactor, the jacket temperature was adjusted to about 20° C., andcontents were allowed to reach an internal temperature of <25° C. A washsolution (22.8% NaCl, 1.5% H₂SO₄, 75.7% water, 300 mL) was charged tothe reactor, and the contents were agitated for about 30 minutes. Thebottom phase was separated, and a second wash solution (22.8% NaCl, 1.5%H₂SO₄, 75.7% water, 300 mL) was charged to the reactor. After agitatingfor about 15 minutes, the bottom phase was separated, and 20% aqueousNaCl (300 mL) was charged to the reactor and agitated for about 15minutes. The bottom phase was separated. Heptane (150 mL) was charged tothe reactor, followed by seed (51 mg, 0.1 wt %). The mixture was agedfor about 30 minutes, during which a slurry formed. Additional heptane(450 mL) was then charged over no less than 30 minutes. The jackettemperature was then adjusted to about 29° C., and solvent was distilledunder vacuum until the reactor contents reached a volume of about 450mL. The slurry was then cooled to an internal temperature of about 5° C.over no less than 1 hour. The reactor contents were discharged andsolids were collected by filtration. The mother liquors were recycledtwice in order to displace solids from the reactor, each time allowingthe internal temperature to reach about <6° C. before discharging. Asolution of heptane/iso-propylacetate (75% v/v, 225 mL) was then chargedto the reactor, and when the internal temperature reached <6° C., theslurry was rinsed forward through the filter cake. The wet cake was thendried under vacuum at about 40° C. for about 18 hours, providing C-1a.

¹H NMR (400 MHz, CDCl₃): δ 7.12 (br, 1H), 6.66 (app t, J=8.1 Hz, 2H),4.50 (app d, J=5.7 Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H).¹³C NMR (100 MHz, CDCl₃): δ 203.96, 164.90, 162.37 (ddd, J=250.0, 15.7,15.7 Hz), 161.71 (ddd, J=250.3, 14.9, 10.9 Hz), 110.05 (ddd, J=19.7,19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t, J=3.5 Hz).LCMS, Calculated: 275.23, Found: 275.97 (M).

N. Enamine Formation of D-1a from C-1a

C-1a (8.4 g, 1.0 equiv) was charged to a reactor, followed by theaddition of 2-methyltetrahydrofuran (166.7 mL, 20 volumes, 0.18 M) andtrifluoroacetic acid (231.9 uL, 0.1 equiv). The reaction mixture washeated to an internal temperature of about 40° C., and DMF-DMA (3.0 mL,0.75 equiv) was quickly added. The reaction mixture is agitated for afew minutes, followed by the addition of D-1a seeds (20 mgs, 0.002equivalent) at about 40° C. The heterogenous mixture was aged at 40° C.for about one hour. An additional portion of DMF-DMA was added (1.5 mL,0.37 equivalent), and the reaction mixture was agitated for about 25minutes. One final portion of DMF-DMA (1.5 mL, 0.37 equiv) was added,and the reaction mixture was cooled from about 40° C. to roomtemperature and allowed to agitate overnight.

The contents of the reactor were filtered, and the filter cake wasrinsed with a solvent combination of 2-methyltetrahydrofuran andheptanes (67.1 mL, 8 volumes) to provide D-1a. ¹H NMR (400 MHz, CDCl₃):δ 8.34 (br, 1H), 7.83 (s, 1H), 6.63 (m, 2H), 4.53 (s, 2H), 4.12 (s, 2H),3.34 (s, 3H), 3.10 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 192.33, 165.85,163.03, 160.54, 158.00, 110.89, 103.50, 100.05, 76.11, 58.77, 44.74,30.61. LCMS, Calculated: 330.12, Found: 330.91 (M).

O. Condensation and Cyclization of D-1a to Form F-1a Via E-1a

D-1a (70.0 g, 212 mmol, 1.0 equivalent) was charged to an inerted 1 Lreactor. To this reactor was then charged methanol (420 mL, 6 volumes)and aminoacetaldehyde dimethylacetal (1, 28.8 mL, 233 mmol, 1.1equivalent). The reactor jacket temperature was maintained between about16 and 23° C.

After aging the reaction for about 1-2 hours, dimethyl oxalate (2, 125g, 1.06 mol, 5.0 equivalents) was charged to the reactor and the reactorjacket temperature was increased to between about 42-48° C. Uponachieving complete dissolution of dimethyl oxalate, the reactor wascharged with sodium methoxide as a solution in methanol (84.7 g, 25 wt%, 197 mmol, 1.85 equivalents). The reactor jacket temperature wasmaintained between about 42-48° C. for about 14-18 h.

Reactor jacket temperature was reduced to about 34-37° C. over thecourse of about 1 h. Upon reaching a stable temperature in this range,the reactor was charged with F-1a seed crystals (0.350 g, ca. 0.5 wt %)and allowed to age for about 1-2 h. At this point, water (420 mL, 6volumes) was charged to the reactor over the course of about 2-3 hours.The reactor jacket temperature was reduced to about 18-22° C. over about1 h.

The resulting slurry was discharged from the reactor, and the solidscollected by filtration. Liquors were recycled to displace solidsremaining in the reactor. The collected solids on the filter were thenwashed with a 1:1 mixture of water and methanol (420 mL, 6 volumes),followed by water (420 mL, 6 V). The collected wet cake was dried in avacuum oven at about 36-42° C. for about 16 h, providing F-1a.

¹H NMR (400 MHz, CDCl₃): δ 10.28 (t, J=5.5 Hz, 1H), 8.38 (s, 1H),6.66-6.53 (m, 2H), 4.58 (d, J=5.6 Hz, 2H), 4.43 (t, J=4.7 Hz, 1H), 4.00(d, J=4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). ¹³C NMR(100 MHz, CDCl₃): δ 173.08, 163.81, 162.17, 162.14 (ddd, J=249.2, 15.6,15.6 Hz), 161.72 (ddd, J=250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98,119.21, 110.53 (ddd, J=19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68,56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15(M+H).

P. Acetal Hydrolysis of F-1a to Form FF-1a:

To a solution of F-1a (10.0 g, 1.0 equivalent) and acetonitrile (50 mL)was added p-Toluenesulfonic acid monohydrate (0.414 g, 0.10 equivalent)and acetic acid (16.3 mL, 12 equivalent). The reaction was then heatedto about 75° C. and aged for about 8-10 hours. Once the reactioncompletion was confirmed by HPLC, the reaction was cooled to roomtemperature and water (60 mL) was added. The mixture was thenconcentrated under reduced pressure to remove acetonitrile. Theresultant slurry was then aged at room temperature for about 2 hours,filtered, washed with water (2×30 mL). The cake was dried in vacuum ovenat about 50° C. for about 10 hours to give FF-1a.

¹H NMR (400 MHz, DMSO-d₆): δ 10.34 (t, J=8.0 Hz, 1H), 8.45 (s, 1H), 7.19(m, 2H), 6.37 (m, 2H), 4.96 (m, 1H), 4.55 (d, J=4.0 Hz, 2H), 3.95 (m,2H), 3.93 (s, 3H). 3.79 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 172.32,163.47, 162.10, 161.93 (dt, J=246, 15.0 Hz), 161.41 (ddd, J=247, 15.0,11.0 Hz), 148.01, 145.57, 135.84, 118.32, 111.48 (td, J=20.0, 5.0 Hz),101.17 (m), 87.99, 60.55, 60.50, 53.98, 30.37. LCMS, Calculated:431.1061, Found: 431.1062 (M+H).

Q. Cyclization of FF-1a and N-1a.BzOH to Form G-1a

FF-1a (90.0 g, 1.0 equiv), N-1a.BzOH (60.7 g, 1.3 equiv), and potassiumacetate (51.3 g, 2.5 equiv) were charged to a reactor. Dichloromethane(DCM, 1.1 L) was charged and the mixture was agitated at about 20° C.until the reaction is complete. A 5% aqueous NaHCO₃ solution (540 mL)was charged to the reactor and the mixture was agitated until the solidscompletely dissolve. The phases were separated and the bottom organicphase was charged back to the reactor. Water (450 mL) was charged to thereactor and the mixture was agitated for about 15 minutes. The phaseswere separated and the organic phase was distilled to dryness.

The crude G-1a was dissolved in dimethylformamide (DMF, 180 mL) and theresulting solution was charged to a reactor containing water (1.1 L)over about 2 hours, while agitating the water. The product slurry wasaged at about 20° C. for about 12 hours and then filtered. The productcake was washed with water (360 mL) and dried to afford G-1a.

¹H NMR (400 MHz, CDCl₃): δ 10.23 (t, J=5.5 Hz, 1H), 8.39 (s, 1H), 6.60(t, J=8.1 Hz, 2H), 5.29 (dd, J=9.5, 3.7 Hz, 2H), 4.57 (d, J=5.4 Hz, 3H),4.33 (dd, J=12.8, 3.8 Hz, 1H), 4.02-3.87 (m, 1H), 3.94 (s, 3H),2.06-1.88 (m, 4H), 1.78 (dd, J=17.2, 7.5 Hz, 1H), 1.55-1.46 (m, 1H). ¹³CNMR (100 MHz, CDCl₃): δ 174.53, 163.75, 162.33 (dd, J=249.4, 15.7, 15.7Hz), 161.86 (ddd, J=250.4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44,129.75, 118.88, 110.58 (ddd, J=19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64,74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS,Calculated: 463.14, Found: 464.15 (M+H).

R. Conversion of (−)-Vince Lactam to b-1a

Wet Pd/C (0.138 kg) was charged to a reactor followed by 2-MeTHF (421kg) and (−)-Vince lactam (55 kg). The vessel was purged with nitrogenfollowed by hydrogen. The contents were adjusted to about 25 to 35° C.and the hydrogen maintained at about 0.30 to 0.35 MPa. After about 6.5h, the reaction was deemed complete by HPLC. The contents were filteredthrough celite (11 kg) and washed with 2-MeTHF (102 kg). The product wasobtained in solution.

A solution of Boc₂O in 2-MeTHF was prepared as follows: Boc₂O (123 kg)was charged to a reactor followed by 2-MeTHF (60 kg). After a solutionwas achieved, it was discharged into a container and rinsed forward with2-MeTHF (44.6 kg) and held until further use.

The solution of the product of the hydrogenation was charged to areactor and concentrated under reduced pressure to about 5 to 6 V at≤45° C. DMAP (0.34 kg) was charged and the mixture warmed to about 45 to50° C. The solution of Boc₂O was added over approximately 2 h and themixture allowed to stir for an additional 2 h at the target temperature.After this time, the reaction was deemed complete by HPLC. 2-MeTHF wascharged (480 kg) and the solution concentrated under reduced pressure toabout 4 to 5 V at about ≤45° C. This process was repeated twice more toremove t-BuOH. 2-MeTHF was charged (278.8 kg) to afford a-1a insolution.

The solution of a-1a was diluted with 2-MeTHF (405.8 kg) and cooled to−10 to 0° C. MeMgBr (35% in 2-MeTHF, 201.3 kg) was added overapproximately 6 h to maintain the temperature at about −10 to 0° C.After the addition was complete, the mixture was stirred for anadditional approximately 1 to 2 h at which time the reaction wascomplete as determined by HPLC. 15% aqueous AcOH (350 kg) was addedmaintaining the temperature at about 0 to 5° C. to adjust the pH toapproximately 7. The layers were separated and the organic layer waswashed with water twice (726 kg total water used). The organic layer wasconcentrated to about 4 to 5 V under reduced pressure at about ≤45° C.The solution was azeotroped with 2-MeTHF three times to about 4 to 5 Veach time (2810 kg 2-MeTHF used). The final solution was concentratedunder reduced pressure to about 2.5 to 3 V. n-Heptane (126 kg) wasslowly added maintaining the temperature at 30 to 35° C. b-1a seeds wereadded (0.7 kg) and the mixture stirred at about 30 to 35° C. for 5 to 10h. Additional n-heptane was added (200.4 kg) maintaining the temperatureat about 30 to 35° C. over approximately 5 h. The contents weredistilled under reduced pressure at about ≤45° C. to about 6 to 7 V.Additional n-heptane was added (243.2 kg) maintaining the temperature atabout 30 to 35° C. over approximately 1 to 2 h. The contents weredistilled under reduced pressure at about ≤45° C. to about 6 to 7 V.Additional n-heptane was added (241.4 kg) maintaining the temperature atabout 30 to 35° C. over approximately 1 to 2 h. The contents weredistilled under reduced pressure at about ≤45° C. to about 6 to 7 V.Additional n-heptane was added (253.6 kg) maintaining the temperature atabout 30 to 35° C. over approximately 1 to 2 h. The contents were cooledto about −5 to 0° C. and held for approximately 1 to 2 h. Product wascollected by filtration, washed with n-heptane (187 kg) at about −5 to0° C., and dried under reduced pressure at about 40 to 45° C. to affordsingle enantiomer b-1a.

S. Conversion of b-1a to cc-1a

b-1a (90.9 kg) and toluene (822 kg) were charged to a reactor andstirred at 25 to 30° C. to achieve a solution. m-CPBA (174 kg) wascharged into the reactor in 5 portions (4 to 6 h between additions). Thereaction was allowed to stir at about 25 to 30° C. until the reactionwas deemed complete by HPLC (approximately 10 to 20 h). 20% NaHSO₃ (428kg) was added maintaining the temperature about below 30° C. and themixture stirred until negative with starch potassium iodide paper. 10%NaOH (698 kg) was added maintaining the temperature about below 30° C.The mixture was stirred for approximately 30 to 60 min. The organiclayer was washed with water (500 kg) and the organic layer concentratedunder reduced pressure at about ≤45° C. to 5 to 6 V. The temperature wasadjusted to 15 to 25° C. to afford the oxidized product in solution.

Water (90 kg), methanol (70 kg), and LiOH.H₂O (29.5 kg) were added tothe solution of the oxidized product and the mixture stirred at 25 to30° C. for 3 to 6 h at which time the reaction was deemed complete byHPLC. Toluene (390 kg) and 25% NaCl (278 kg) were added to the mixtureand stirred for about 30 to 60 min. The layers were separated and 20%NaCl (259 kg) were added to the organic layer. The pH of the solutionwas adjusted to about 7 to 8 with 1 N HCl (7.6 kg) and the layersseparated. The organic layer was washed with 20% NaCl (259.4 kg). Theorganic layer was filtered and concentrated under reduced pressure atabout ≤45° C. to about 4.5 to 5.5 V. Toluene (385.6 kg) was charged andthe distillation/toluene addition were repeated until KF≤0.05%. Toluene(385.3 kg) was charged followed by active carbon (6.5 kg). The mixturewas warmed to about 30 to 40° C. and stirred for about 2 to 6 h. Thecontents were cooled, filtered through celite (6.3 kg), and washed withtoluene (146 kg). The filtrate was concentrated under reduced pressureat about ≤45° C. to about 1.5 to 1.6 V. The mixture was stirred forabout 30 to 60 min at about 30 to 35° C. n-Heptane (87 kg) was chargedover about 1 to 2 h and the mixture seeded with cc-1a (0.516 kg) andstirred for an additional 2 to 3 h. n-Heptane (286.4 kg) was slowlycharged and stirred for about 2 to 3 h. The mixture was cooled to about10 to 15° C. and stirred for an additional about 3 to 5 h. The productwas collected by filtration and washed with n-heptane (40 kg) at about10 to 15° C. The product was dried under reduced pressure at about 35 to45° C. to afford single enantiomer cc-1a.

T. Classical Resolution of c-1a

A vessel was charged with c-1a (10.0 g, 1 equivalent), (S)-Naproxen(11.5 g, 1.03 mmol) and water (200 mL). The mixture was refluxedovernight, after which the mixture had turned dark. Removal of thesolvent by rotary evaporation yielded the desired salt as a brown solid.The mixture of dd-2a and dd-1a (3.0 g) was suspended in MEK (50 mL) andthe mixture was heated to reflux. Water was added (4 mL). The mixturewas allowed to cool to room temperature. The solid was isolated byfiltration, dried and recrystallized from 10% water in MEK (30 mL) toafford dd-1a which showed an optical purity >90% ee.

U. Classical Resolution of c-1a

To a solution of c-1a (89.7 mgs, 1.0 equiv) in IPA (0.9 mL) was quicklyadded a solution of S-(+)-mandelic acid (134.9 mgs, 1.0 equiv) in IPA(0.9 mL). The mixture was stirred at approximately room temperature andsolid precipitate was observed after approximately 20 minutes. Theslurry was stirred for an additional 15 minutes, and the solids werefiltered and collected. The solids obtained from the initial saltformation were recrystallized in IPA and was slowly cooled fromapproximately 80° C. to approximately 0° C. to provide theenantioenriched product dd-1b.

V. Enzymatic Resolution of c-1a—Selective Acylation

Toluene (500 mL) was added to a reaction vessel followed by c-1a (50 g,1 eq.). Glutaric anhydride (28.4 g, 1 eq.) was added followed byNovozyme 435 (7.5 g, 15 wt %). The reaction was allowed to stir forapproximately 23 h at approximately 10 to 15° C. Additional Novozyme(2.5 g, 5 wt %) was charged and the reaction allowed to proceed forapproximately 12 h at approximately 10 to 15° C. Solids were removed byfiltration and rinsed with toluene (100 mL). The organic phase waswashed with 10% Na₂CO₃ (250 mL) followed by 5% Na₂CO₃ (250 mL). Thecombined aqueous phases were washed with MTBE (2×500 mL). THF (150 mL)was added to the resulting aqueous phase followed by sodium hydroxide(14.9 g, 3 equivalents). The mixture was allowed to stir forapproximately 4 h at approximately 15 to 20° C. The layers wereseparated, and the THF layer was concentrated. The aqueous layer wasextracted with dichloromethane (2×250 mL). The residue from the THFlayer was dissolved in the combined dichloromethane, and the mixturewashed with water (250 mL). The organic phase was concentrated toapproximately 100 mL and water (300 mL) was added. The mixture wasfurther concentrated to approximately 250 mL at approximately 55 to 60°C. The mixture was cooled to approximately 47° C. over approximately 1h, seeds of the product (200 mg) were added and the mixture aged forapproximately 1 h at approximately 45 to 47° C. The mixture was cooledto approximately 25° C. over approximately 2 h and aged approximately0.5 h. The solids were collected by filtration and washed with water (50mL). The product was dried at approximately 35 to 40° C. under vacuum toafford the desired product cc-1a (>95% ee).

W. Enzymatic Resolution of c-1a—Selective Hydrolysis

A mixture of compound c-1a (50 g, 1 eq.), glutaric anhydride (42.5 g,1.5 eq.) and DMAP (50 mg, 0.001 eq.) in 300 mL pyridine was stirredovernight at approximately 60° C. The reaction mixture was evaporated todryness. Subsequently the residue was dissolved in DCM (250 mL) andwashed with 3×250 mL 0.2 M HCl (aq.). The organic layer was evaporatedto dryness. The residue was stirred with 300 mL water and the pH wasadjusted to 7.8 with approximately 300 mL 2 M NaOH solution. The waterlayer was washed with DCM (3×70 mL). The water layer was then acidifiedto pH 4 with 3 N HCl(aq) and extracted with DCM (4×150 mL and 2×100 mL).The combined organic layers were dried over Na₂SO₄, filtered andevaporated, yielding a colorless oil which crystalized upon standing.Trituration with pentane (˜100 mL) followed by filtration and dryingunder vacuum yielded racemic ee-1a.

Racemic ee-1a (1.008 g) was suspended in diisopropyl ether (10 mL). Tothe suspension was added 200 mM sodium phosphate buffer pH 7 (20 mL) andCal-B (0.2 g). The reaction mixture was shaken at 250 rpm, 30° C. for˜100 h (>80% ee observed after 91.5 h). The reaction mixture wasfiltered and the layers of the filtrate were separated. The solid waswashed with DCM (2×10 mL). The filtrate was used to extract the aqueouslayer. The aqueous layer was extracted a second time with DCM (10 mL).The combined organic layers were washed with 5% Na₂CO₃ (2×20 mL), brine(10 mL) and dried over Na₂SO₄. Filtration and evaporation of thevolatiles under reduced pressure afforded the desired product cc-1a.

X. Allylic Amination of f-1a to Form g-1a

Triphenylphosphine (0.37 g, 0.02 eq) and Pd₂(dba)₃ (0.32 g, 0.005 eq)were mixed in degassed THF (200 mL) at approximately room temperaturefor approximately 20 min. f-1a (10 g, 1 eq, single enantiomer), Cs₂CO₃(46 g, 2 eq) and di-tert-butyl iminodicarboxylate (16.05 g, 1.05 eq)were added and the mixture heated to 50° C. for approximately 18 h. Themixture was cooled and water (100 mL) and ethyl acetate (50 mL) wereadded. The layers were separated and the organic phase was washed 2×ethyl acetate. The combined organics were dried over sodium sulfate andconcentrated to dryness. The residue was purified by silica gel columnchromatography (0 to 40% ethyl acetate in hexane). The isolated materialwas dissolved in MeTHF, washed with 5% aq. KOH, concentrated, andpurified by silica gel column chromatography (0 to 10% methanol indichloromethane) to provide the desired product g-1a.

Y. Hydrogenation of g-1a to Form h-1a

g-1a (1.0 g) and PtO₂ (0.008 g) were combined in isopropanol (10 mL).The vessel was flushed with H₂ gas and stirred under an atmosphere ofhydrogen at approximately room temperature for approximately 18 h. Themixture was filtered through celite and used without furtherpurification in the subsequent deprotection.

Z. Deprotection of h-1a to Form N-1a

Acetyl chloride (1.7 mL, 7 eq) was combined with isopropanol (5 mL) andstirred at approximately room temperature for approximately 15 min togenerate HCl in isopropanol. Crude starting material h-1a in isopropanol(2.5 mL) was added and rinsed forward with isopropanol (2.5 mL). Afterapproximately 18 h, the slurry was cooled to approximately 0° C. andN-1a was collected by filtration. ¹H NMR (CD₃OD) confirmed the desiredproduct was isolated.

Each of the references including all patents, patent applications andpublications cited in the present application is incorporated herein byreference in its entirety, as if each of them is individuallyincorporated. Further, it would be appreciated that, in the aboveteaching of invention, the skilled in the art could make certain changesor modifications to the invention, and these equivalents would still bewithin the scope of the disclosure defined by the appended claims of theapplication.

The invention claimed is:
 1. A process to prepare a compound of FormulaI:

according to the following General Scheme VI

wherein the process comprises the following steps: reacting B-1.J-1 inthe presence of an acid to yield C-1; reacting C-1 with an alkylatedformamide acetal to yield D-1; reacting D-1 with K-1 to yield E-1;reacting E-1 with M-1 in the presence of a base to yield F-1; reactingF-1 with at least one acid to yield FF-1; reacting FF-1 with N-1, or asalt or a co-crystal thereof, in the presence of an additive selectedfrom the group consisting of a carboxylate salt, an inorganic carbonate,a metal hydride, an alkoxide, a water scavenger and a mixture thereof toyield G-1; and reacting G-1 with at least one reagent selected from thegroup consisting of metal salts, Lewis acids, sodium ethanethiolate,sodium hexamethyldisiloxane, trifluoroacetic acid, and combinationsthereof to yield a compound of Formula I; wherein Hal is halogen, whichmay be the same or different, n is 1, 2, or 3, L is —C(R^(c))₂—,—C(R^(c))₂C(R^(c))₂—, —C(R^(c))₂C(R^(c))₂C(R^(c))₂—, or—C(R^(c))₂C(R^(c))₂C(R^(c))₂C(R^(c))₂—, each R^(c) is, independently,hydrogen, halo, hydroxyl or C₁-C₄alkyl, each R^(a), R¹, and R² is,independently, (C₁-C₄)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl (C₁-C₄)alkyl;and each R^(b) is independently (C₁-C₄)alkyl.
 2. The process of claim 1wherein B1.J-1 is reacted in the presence of an acid selected from thegroup consisting of an inorganic acid, an organic acid, a halogenatedorganic acid, a Lewis acid and mixtures thereof.
 3. The process of claim2 wherein the acid is selected from the group consisting of hydrochloricacid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid,formic acid, trifluoroacetic acid, trichloroacetic acid,perfluoropropionic acid, dichloroacetic acid, chloroacetic acid, aceticacid, para-toluenesulfonic acid, methane sulfonic acid, zinc chloride,magnesium bromide, magnesium triflate, copper triflate, scandiumtriflate, and a mixture thereof.
 4. The process of claim 3 wherein theacid is trifluoroacetic acid.
 5. The process of claim 1 wherein thealkylated formamide acetal is selected from the group consisting ofN,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethylacetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamidedimethyl acetal, and N,N-diisopropylformamide dimethyl acetal.
 6. Theprocess of claim 5 wherein the alkylated formamide acetal isN,N-dimethylformamide dimethyl acetal.
 7. The process of claim 1 whereinC-1 is reacted with an alkylated formamide acetal in the presence of anacid.
 8. The process of claim 7 wherein the acid is selected from thegroup consisting of trifluoroacetic acid, formic acid, acetic acid,sulfuric acid trifluoroacetic acid, trichloroacetic acid, andperfluoropropionic acid.
 9. The process of claim 8, wherein the acid istrifluoroacetic acid.
 10. The process of claim 1 wherein K-1 is selectedfrom the group consisting of aminoacetaldehyde diethylacetal,aminoacetaldehyde dipropylacetal, aminoacetaldehyde dimethylacetal, andaminoacetaldehyde dibutalacetal.
 11. The process of claim 10 wherein K-1is aminoacetaldehyde dim ethyl acetal.
 12. The process of claim 1wherein M-1 is selected from the group consisting of dimethyl oxalate,diethyl oxalate, dipropyl oxalate, and dibutyl oxalate.
 13. The processof claim 12 wherein M-1 is dimethyl oxalate.
 14. The process of claim 1wherein E-1 is reacted with M-1 in the presence of a base selected fromthe group consisting of a metal hydride, an alkoxide, an inorganiccarbonate, a bis(trialkylsilyl)amide base, and a mixture thereof. 15.The process of claim 14 wherein the base is selected from the groupconsisting of sodium hydride, potassium hydride, lithium hydride, sodiummethoxide, sodium tert-butoxide, sodium ethoxide, potassiumtert-butoxide, potassium ethoxide, sodium tert-pentoxide, lithiumtert-butoxide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate, anda mixture thereof.
 16. The process of claim 15, wherein the base issodium methoxide.
 17. The process of claim 1 wherein F-1 is reacted withat least one acid selected from the group consisting of an organic acid,an inorganic acid, an organic carboxylic acids, and mixtures thereof.18. The process of claim 17 wherein the at least one acid is selectedfrom the group consisting of methanesulfonic acid, acetic acid,trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formicacid, butyric acid, propionic acid, benzoic acid, p-Toluenesulfonicacid, camphorsulfonic acid, and mixtures thereof.
 19. The process ofclaim 18, wherein the at least one acid is p-toluenesulfonic acid. 20.The process of claim 1 wherein L is —CH₂—CH₂—.
 21. The process of claim1 wherein N-1 is


22. The process of claim 1 wherein N-1 is in the form of a salt orco-crystal.
 23. The process of claim 22 wherein N-1 is


24. The process of claim 1 wherein N-1 is in solution.
 25. The processof claim 1 wherein the additive is selected from the group consisting oflithium carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydride, potassium hydride, lithium hydride, sodiummethoxide, sodium tert-butoxide, sodium ethoxide, potassiumtert-butoxide, potassium ethoxide, sodium tert-pentoxide, lithiumtert-butoxide, sodium propionate, potassium propionate, molecularsieves, trimethyl orthoacetate, potassium acetate, sodium acetate,lithium acetate and trimethyl orthoformate.
 26. The process of claim 25wherein the additive is potassium acetate.
 27. The process of claim 1,wherein the at least one reagent is selected from the group consistingof magnesium bromide, lithium chloride, lithium bromide, lithium iodide,aluminum trichloride, aluminum tribromide, chlorotrimethylsilane,iodotrimethylsilane, boron trichloride, boron tribromide, sodiumethanethiolate, sodium hexamethyldisiloxane, palladium, borontrifluoride diethyl etherate, and trifluoroacetic acid.
 28. The processof claim 27, wherein the at least one reagent is magnesium bromide. 29.The process of claim 1 wherein each R^(a), R^(b), R¹, and R² is,independently (C₁-C₄)alkyl.
 30. The process of claim 29 wherein R² is—CH₃.
 31. The process of claim 29 wherein R¹ is —CH₃.
 32. The process ofclaim 29 wherein R^(a) is —CH₃.
 33. The process of claim 29 whereinR^(b) is —CH₃.
 34. The process of claim 1 wherein each Hal isindependently —F or —Cl.
 35. The process of claim 34 wherein Hal is F.36. The process of claim 1 wherein n is
 3. 37. The process of claim 1wherein J-1 is


38. The process of claim 18, wherein the at least one acid is formicacid.
 39. The process of claim 27, wherein the at least one reagent islithium chloride.